Dihydropteridinone derivatives and uses thereof

ABSTRACT

The present disclosure provides compounds of Formula (I), and pharmaceutically compositions thereof. Compounds of Formula (I) have been found to bind bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits of the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, neurological diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § § 120 and365(c) to and is a continuation of international PCT Application,PCT/US2015/044303, filed Aug. 7, 2015, which claims priority under 35U.S.C. § 119(e) to U.S. provisional application, Ser. No. 62/034,821,filed Aug. 8, 2014, each of which is incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under contract numbersU54 CA156732 and U01 HD076508 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Bromodomain-containing proteins are of substantial biological interest,as components of transcription factor complexes and determinants ofepigenetic memory. For example, the bromo and extra terminal (BET)protein family (e.g., bromodomain-containing protein 2 (BRD2),bromodomain-containing protein 3 (BRD3), bromodomain-containing protein4 (BRD4), and bromodomain testis-specific protein (BRDT)) shares acommon domain architecture featuring two amino-terminal bromodomainsthat exhibit high levels of sequence conservation, and a more divergentcarboxy-terminal recruitment domain (Filippakopoulos et al., Nature2010, 468, 1067-1073). BRD2 and BRD3 are reported to associate withhistones along actively transcribed genes and may be involved infacilitating transcriptional elongation (Leroy et al., Mol. Cell. 2008,30, 51-60). It has also been reported that BRD4 or BRD3 may fuse withnuclear protein in testis (NUT), forming novel fusion oncogenes BRD4-NUTor BRD3-NUT, in a highly malignant form of epithelial neoplasia (Frenchet al., Cancer Res., 2003, 63, 304-307; French et al., J. Clin. Oncol.2004, 22, 4135-4139). Data suggests that BRD-NUT fusion proteinscontribute to carcinogenesis (French et al., Oncogene 2008, 27,2237-2242). BRDT is uniquely expressed in the testes and ovary. Allfamily members of BET have been reported to have some function incontrolling or executing aspects of the cell cycle and have been shownto remain in complex with chromosomes during cell division, suggesting arole in the maintenance of epigenetic memory. In addition, some virusesmake use of BET proteins to tether their genomes to the host cellchromatin, as part of the process of viral replication (You et al., Cell2004, 117, 349-360). BRD4 appears to be involved in the recruitment ofthe pTEF-b complex to inducible genes, resulting in phosphorylation ofRNA polymerase and increased transcriptional output (Hargreaves et al.,Cell 2009, 138, 129-145). In humans, BRD2, BRD3, BRD4, and BRDT exhibitsimilar gene arrangements, domain organizations, and some functionalproperties (Wu et al., J. Biol. Chem. 2007, 282, 13141-13145).

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I). The compoundsdescribed herein are thought to be binders of transcription factors,such as bromodomain-containing proteins (e.g., BET proteins) and may beuseful in male contraception and in treating and/or preventing a widerange of diseases (e.g., diseases associated with bromodomains, diseasesassociated with the activity (e.g., aberrant activity) of bromodomains,diseases associated with bromodomain-containing proteins, and diseaseassociated with the activity (e.g., aberrant activity) ofbromodomain-containing proteins). Diseases that may be treated and/orprevented by the methods of the disclosure include, but are not limitedto, proliferative diseases (e.g., cancers, benign neoplasms,pathological angiogenesis, inflammatory diseases, and autoimmunediseases), cardiovascular diseases, viral infections, fibrotic diseases,neurological diseases, metabolic diseases, endocrine diseases, andradiation poisoning. Also provided in the present disclosure arepharmaceutical compositions, kits, methods, and uses including or usinga compound described herein.

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(A), R^(B), R^(C), R¹, R², R³, L¹,R^(B1), R^(B3), and p are as described herein.

Exemplary compounds of Formula (I) include, but are not limited to,those of Tables A, B, and C and pharmaceutically acceptable salts,solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled derivatives, and prodrugs thereof.

The compounds described herein may bind bromodomain-containing proteins.In certain embodiments, the compounds described herein bind to abromodomain (e.g., a bromodomain of a bromodomain-containing protein).The compounds described herein may inhibit the activity of thebromodomain-containing proteins. The compounds described herein may alsoinhibit the function (e.g., dysfunction) of a bromodomain.

In still another aspect, the present disclosure provides pharmaceuticalcompositions including a compound described herein, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical compositions described herein include a therapeuticallyor prophylactically effective amount of a compound described herein. Thepharmaceutical composition may be useful for treating and/or preventinga disease in a subject in need thereof. The pharmaceutical compositionmay also be useful in inhibiting the replication of a virus, in killinga virus, in inhibiting the activity of a bromodomain-containing protein,in inhibiting the activity of a bromodomain, in inhibiting the bindingof a bromodomain of a bromodomain-containing protein to an acetylatedlysine residue of a histone or other protein, in modulating (e.g.,inhibiting) transcriptional elongation, in modulating (e.g.,down-regulating or inhibiting) the expression (e.g., transcription) of agene that is regulated by a bromodomain-containing protein, in inducingapoptosis, and/or inducing G1 arrest, in a subject or cell.

In certain embodiments, the disease described herein is associated withthe activity (e.g., aberrant activity, increased activity) of abromodomain-containing protein. In certain embodiments, the disease isassociated with the function (e.g., dysfunction) of abromodomain-containing protein. In certain embodiments, the disease isassociated with the activity (e.g., aberrant activity, increasedactivity) of a bromodomain. In certain embodiments, the disease isassociated with the function (e.g., dysfunction) of a bromodomain.

In certain embodiments, the disease is a proliferative disease (e.g.,cancer, benign neoplasm, pathological angiogenesis, an inflammatorydisease, or an autoimmune disease), cardiovascular disease, viralinfection, fibrotic disease, neurological disease, metabolic disease,endocrine disease, or radiation poisoning.

In certain embodiments, the subject is a mammal. In certain embodiments,the subject is a human. In certain embodiments, the subject is anon-human animal. In certain embodiments, the cell is present in vitro.In certain embodiments, the cell is present in vivo.

Another aspect of the present disclosure relates to methods of treatinga disease in a subject in need thereof.

In another aspect, the present disclosure provides methods of preventinga disease in a subject in need thereof.

Another aspect of the present disclosure relates to methods of reducingthe risk of developing a disease in a subject in need thereof.

Another aspect of the present disclosure relates to methods ofinhibiting the replication of a virus (e.g., human immunodeficiencyvirus (HIV), human papillomavirus (HPV), hepatitis C virus (HCV), herpessimplex virus (HSV), Ebola virus, and influenza virus).

Another aspect of the present disclosure relates to methods of killing avirus (e.g., human immunodeficiency virus (HIV), human papillomavirus(HPV), hepatitis C virus (HCV), herpes simplex virus (HSV), Ebola virus,and influenza virus).

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain-containing protein in a subject or cell.In certain embodiments, the activity of a bromodomain-containing proteinis aberrant or unwanted activity (e.g., an increased activity) of thebromodomain-containing protein. In certain embodiments, the activity ofthe bromodomain-containing protein is selectively inhibited (e.g., whencompared to the activity of a kinase that is different from thebromodomain-containing protein) by the methods.

In yet another aspect, the present disclosure provides methods ofinhibiting the activity of a bromodomain in a subject or cell. Incertain embodiments, the activity of a bromodomain being inhibited isaberrant or unwanted activity (e.g., an increased activity) of thebromodomain.

In yet another aspect, the present disclosure provides methods ofinhibiting the binding of a bromodomain to an acetylated lysine residueof a second protein (e.g., histone) in a subject or cell. In certainembodiments, the second protein is a protein that includes at least oneacetylated lysine residue.

In still another aspect, the present disclosure provides methods ofmodulating the expression (e.g., transcription) of a gene that isregulated by a bromodomain-containing protein in a subject or cell. Incertain embodiments, the methods of modulating the expression (e.g.,transcription) of a gene are methods of down-regulating or inhibitingthe expression (e.g., transcription) of the gene. The method may resultin decreased levels of a gene product (e.g., RNA, protein) in a cell.

In still another aspect, the present disclosure provides methods ofmodulating (e.g., inhibiting) transcriptional elongation in a subject orcell.

Another aspect of the disclosure relates to methods of inducingapoptosis (e.g., apoptosis of a cancer cell) in a subject.

Another aspect of the disclosure relates to methods of inducingapoptosis of a cell (e.g., an in vitro cell, a cancer cell).

Another aspect of the disclosure relates to methods of method forinducing G1 arrest in a subject or cell.

The methods of the present disclosure include administering to thesubject an effective amount of a compound or pharmaceutical compositiondescribed herein. The methods of the present disclosure includecontacting a cell with an effective amount of a compound orpharmaceutical composition described herein. The methods of the presentdisclosure include contacting a virus with an effective amount of acompound or pharmaceutical composition described herein. In certainembodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylacticallyeffective amount. In certain embodiments, the methods of the presentdisclosure further include administering to the subject an additionalpharmaceutical agent in combination with a compound or pharmaceuticalcomposition described herein. In certain embodiments, the methods of thepresent disclosure further include contacting a cell with an additionalpharmaceutical agent in combination with a compound or pharmaceuticalcomposition described herein. In certain embodiments, the methods of thepresent disclosure further include contacting a virus with an additionalpharmaceutical agent in combination with a compound or pharmaceuticalcomposition described herein. In certain embodiments, the combination ofthe pharmaceutical agent and the compound or pharmaceutical compositiondescribed herein is synergistic.

Another aspect of the disclosure relates to methods of screening alibrary of compounds to identify a compound that is useful in a methodof the disclosure.

Another aspect of the present disclosure relates to kits comprising acontainer with a compound or pharmaceutical composition describedherein. The kits described herein may include a single dose or multipledoses of the compound or pharmaceutical composition described herein.The provided kits may be useful in a method of the disclosure. Incertain embodiments, the kit further includes instructions for using thekit.

In yet another aspect, the present disclosure provides compounds andpharmaceutical compositions described herein for use in a method of thedisclosure.

The present application refers to various issued patents, publishedpatent applications, journal articles, and other publications, all ofwhich are incorporated herein by reference. The details of one or moreembodiments of the disclosure are set forth herein. Other features,objects, and advantages of the disclosure will be apparent from theDetailed Description, the Figures, the Examples, and the Claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the platemaps for acyl hydrazone condensations andsubsequent screening in BRD4 and BRDT inhibition assays. FIG. 1A showsplate map 1. FIG. 1B shows plate map 2. FIG. 1C shows plate map 3. FIG.1D shows plate map 4.

FIG. 2 shows percent inhibition values (measured in luminescence) ofrepresentative compounds of Formula (I) against BRD4 in an ALPHA assay.

FIGS. 3A and 3B show biological activity of representative compounds ofFormula (I) against BRD4 in an ALPHA assay. FIG. 3A showsDMSO-normalized luminescence at 50 μM (top panel) and 2.5 μM (bottompanel) of the compounds. FIG. 3B shows DMSO-normalized luminescence at125 nM (top panel) and 6.3 nM (bottom panel) of the compounds.

FIGS. 4A and 4B show biological activity of representative compounds ofFormula (I) against BRDT in an ALPHA assay. FIG. 4A showsDMSO-normalized luminescence at 50 μM (top panel) and 2.5 μM (bottompanel) of the compounds. FIG. 4B shows DMSO-normalized luminescence at125 nM (top panel) and 6.3 nM (bottom panel) of the compounds.

DEFINITIONS

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

In a formula,

is a single bond where the stereochemistry of the moieties immediatelyattached thereto is not specified. Such a

bond may be

or

.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

The term “aliphatic” includes both saturated and unsaturated, straightchain (i.e., unbranched), branched, acyclic, cyclic, or polycyclicaliphatic hydrocarbons, which are optionally substituted with one ormore functional groups. As will be appreciated by one of ordinary skillin the art, “aliphatic” is intended herein to include, but is notlimited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties. Thus, the term “alkyl” includes straight,branched and cyclic alkyl groups. An analogous convention applies toother generic terms such as “alkenyl”, “alkynyl”, and the like.Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the likeencompass both substituted and unsubstituted groups. In certainembodiments, “lower alkyl” is used to indicate those alkyl groups(cyclic, acyclic, substituted, unsubstituted, branched or unbranched)having 1-6 carbon atoms. In certain embodiments, the alkyl, alkenyl, andalkynyl groups employed in the disclosure contain 1-20 aliphatic carbonatoms. In certain other embodiments, the alkyl, alkenyl, and alkynylgroups employed in the disclosure contain 1-10 aliphatic carbon atoms.In yet other embodiments, the alkyl, alkenyl, and alkynyl groupsemployed in the disclosure contain 1-8 aliphatic carbon atoms. In stillother embodiments, the alkyl, alkenyl, and alkynyl groups employed inthe disclosure contain 1-6 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-4 carbon atoms. Illustrative aliphatic groups thusinclude, but are not limited to, for example, methyl, ethyl, n-propyl,isopropyl, cyclopropyl, —CH₂-cyclopropyl, vinyl, allyl, n-butyl,sec-butyl, isobutyl, tert-butyl, cyclobutyl, —CH₂-cyclobutyl, n-pentyl,sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, —CH₂— cyclopentyl,n-hexyl, sec-hexyl, cyclohexyl, —CH₂-cyclohexyl moieties and the like,which again, may bear one or more substituents. Alkenyl groups include,but are not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like. Representative alkynyl groupsinclude, but are not limited to, ethynyl, 2-propynyl (propargyl),1-propynyl, and the like.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂ ₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁ ₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, thealkyl group is a substituted C₁₋₁₀ alkyl (such as substituted C₁₋₆alkyl, e.g., —CF₃, Bn).

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl. Inan alkenyl group, a C═C double bond for which the stereochemistry is notspecified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂ ₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀ carbocyclyl”).Exemplary C₃₋₆ carbocyclyl groups include, without limitation,cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl(C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆),cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C₃₋₈carbocyclyl groups include, without limitation, the aforementioned C₃ 6carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl(C₈), and the like. Exemplary C₃₋₁₀ carbocyclyl groups include, withoutlimitation, the aforementioned C₃₋₈ carbocyclyl groups as well ascyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl(C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀),spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C). Examples of C₃₋₆ cycloalkylgroups include the aforementioned C₅₋₆ cycloalkyl groups as well ascyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groupsinclude the aforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl(C₇) and cyclooctyl (C₈). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group isunsubstituted C₃₋₁₀ cycloalkyl. In certain embodiments, the cycloalkylgroup is substituted C₃₋₁₀ cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system,such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pielectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl and refers to an optionallysubstituted alkyl group substituted by an optionally substituted arylgroup. In certain embodiments, the aralkyl is optionally substitutedbenzyl. In certain embodiments, the aralkyl is benzyl. In certainembodiments, the aralkyl is optionally substituted phenethyl. In certainembodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to anoptionally substituted alkyl group substituted by an optionallysubstituted heteroaryl group.

“Unsaturated” or “partially unsaturated” refers to a group that includesat least one double or triple bond. A “partially unsaturated” ringsystem is further intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl groups). Likewise, “saturated” refers to a group that doesnot contain a double or triple bond, i.e., contains all single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, which are divalent bridging groups, are further referred tousing the suffix-ene, e.g., alkylene, alkenylene, alkynylene,carbocyclylene, heterocyclylene, arylene, and heteroarylene.

An atom, moiety, or group described herein may be unsubstituted orsubstituted, as valency permits, unless otherwise provided expressly.The term “optionally substituted” refers to substituted orunsubstituted.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionallysubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted”or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, any of the substituents described herein thatresults in the formation of a stable compound. The present disclosurecontemplates any and all such combinations in order to arrive at astable compound. For purposes of this disclosure, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety. In certain embodiments, thesubstituent is a carbon atom substituent. In certain embodiments, thesubstituent is a nitrogen atom substituent. In certain embodiments, thesubstituent is an oxygen atom substituent. In certain embodiments, thesubstituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂,—NR^(bb)P(═O)(R^(aa))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂, —P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄, —P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃⁺X⁻, —OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄,—B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion; or two geminal hydrogens on a carbon atom are replaced withthe group ═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa),═NNR^(bb)C(═O)OR^(aa), ═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(CC))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆ ₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

-   -   each instance of R^(dd) is, independently, selected from        halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee),        —ON(R^(ff))₂, —N(R^(ff))₂, —N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff),        —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee), —CO₂H, —CO₂R^(ee),        —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂,        —NR^(ff)C(═O)R^(cc), —NR^(ff)CO₂R^(cc), —NR^(ff)C(═O)N(R^(ff))₂,        —C(═NR^(ff))OR^(cc), —OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee),        —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,        —NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee),        —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),        —S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,        —C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,        —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆        alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀        carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10        membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,        heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,        heterocyclyl, aryl, and heteroaryl is independently substituted        with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd)        substituents can be joined to form ═O or ═S; wherein X⁻ is a        counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻,sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄ ⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, andcarborane anions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplarycounterions which may be multivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻,B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻, carboxylate anions (e.g., tartrate, citrate,fumarate, maleate, malate, malonate, gluconate, succinate, glutarate,adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates,aspartate, glutamate, and the like), and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of—C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or —C(═S)SR^(aa), wherein R^(aa) andR^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa),R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1, 1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbarnate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzene sulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

Exemplary oxygen atom substituents include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, wherein X⁻,R^(aa), R^(bb), and R^(cc) are as defined herein. In certainembodiments, the oxygen atom substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference. Exemplary oxygen protecting groupsinclude, but are not limited to, methyl, t-butyloxycarbonyl (BOC orBoc), methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-forrnylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

Exemplary sulfur atom substituents include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. In certainembodiments, the sulfur atom substituent present on a sulfur atom is asulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

The term “leaving group” is given its ordinary meaning in the art ofsynthetic organic chemistry and refers to an atom or a group capable ofbeing displaced by a nucleophile. See, for example, Smith, MarchAdvanced Organic Chemistry 6th ed. (501-502). Examples of suitableleaving groups include, but are not limited to, halogen (such as F, Cl,Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy,alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, andhaloformates. In some cases, the leaving group is a sulfonic acid ester,such as toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate,—OMs), p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS(═O)₂(CF₂)₃CF₃(nonaflate, —ONf), or trifluoromethanesulfonate (triflate, —OTf). Insome cases, the leaving group is a brosylate, such asp-bromobenzenesulfonyloxy. In some cases, the leaving group is anosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, theleaving group is a sulfonate-containing group. In some embodiments, theleaving group is a tosylate group. The leaving group may also be aphosphineoxide (e.g., formed during a Mitsunobu reaction) or an internalleaving group such as an epoxide or cyclic sulfate. Other non-limitingexamples of leaving groups are water, ammonia, alcohols, ether moieties,thioether moieties, zinc halides, magnesium moieties, diazonium salts,and copper moieties. Additional exemplary leaving groups include, butare not limited to, activated substituted hydroxyl groups (e.g.,—OC(═O)SR^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂,—OS(═O)R^(aa), —OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein).

The disclosure is not intended to be limited in any manner by the aboveexemplary listing of substituents.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds describedherein include those derived from suitable inorganic and organic acidsand bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound, or salt thereof,that are associated with a solvent, usually by a solvolysis reaction.This physical association may include hydrogen bonding. Conventionalsolvents include water, methanol, ethanol, acetic acid, DMSO, THF,diethyl ether, and the like. The compounds described herein may beprepared, e.g., in crystalline form, and may be solvated. Suitablesolvates include pharmaceutically acceptable solvates and furtherinclude both stoichiometric solvates and non-stoichiometric solvates. Incertain instances, the solvate will be capable of isolation, forexample, when one or more solvent molecules are incorporated in thecrystal lattice of a crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Representative solvates includehydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R·x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2H₂O) and hexahydrates (R.6H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof). All polymorphs have the sameelemental composition. Different crystalline forms usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Various polymorphs of a compound can beprepared by crystallization under different conditions.

The term “prodrugs” refers to compounds that have cleavable groups andbecome by solvolysis or under physiological conditions the compoundsdescribed herein, which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives andthe like, N-alkylmorpholine esters and the like. Other derivatives ofthe compounds described herein have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds described herein are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

The term “small molecule” refers to molecules, whethernaturally-occurring or artificially created (e.g., via chemicalsynthesis) that have a relatively low molecular weight. Typically, asmall molecule is an organic compound (i.e., it contains carbon). Thesmall molecule may contain multiple carbon-carbon bonds, stereocenters,and other functional groups (e.g., amines, hydroxyl, carbonyls, andheterocyclic rings, etc.). In certain embodiments, the molecular weightof a small molecule is at most about 1,000 g/mol, at most about 900g/mol, at most about 800 g/mol, at most about 700 g/mol, at most about600 g/mol, at most about 500 g/mol, at most about 400 g/mol, at mostabout 300 g/mol, at most about 200 g/mol, or at most about 100 g/mol. Incertain embodiments, the molecular weight of a small molecule is atleast about 100 g/mol, at least about 200 g/mol, at least about 300g/mol, at least about 400 g/mol, at least about 500 g/mol, at leastabout 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, orat least about 900 g/mol, or at least about 1,000 g/mol. Combinations ofthe above ranges (e.g., at least about 200 g/mol and at most about 500g/mol) are also possible. In certain embodiments, the small molecule isa therapeutically active agent such as a drug (e.g., a molecule approvedby the U.S. Food and Drug Administration as provided in the Code ofFederal Regulations (C.F.R.)). The small molecule may also be complexedwith one or more metal atoms and/or metal ions. Preferred smallmolecules are biologically active in that they produce a biologicaleffect in animals, preferably mammals, more preferably humans. Smallmolecules include, but are not limited to, radionuclides and imagingagents. In certain embodiments, the small molecule is a drug.Preferably, though not necessarily, the drug is one that has alreadybeen deemed safe and effective for use in humans or animals by theappropriate governmental agency or regulatory body. For example, drugsapproved for human use are listed by the FDA under 21 C.F.R. §§330.5,331 through 361, and 440 through 460, incorporated herein by reference;drugs for veterinary use are listed by the FDA under 21 C.F.R. §§500through 589, incorporated herein by reference. All listed drugs areconsidered acceptable for use in accordance with the present disclosure.

A “protein,” “peptide,” or “polypeptide” comprises a polymer of aminoacid residues linked together by peptide bonds and refers to proteins,polypeptides, and peptides of any size, structure, or function.Typically, a protein will be at least three amino acids long. A proteinmay refer to an individual protein or a collection of proteins. Proteinsdescribed herein preferably contain only natural amino acids, althoughnon-natural amino acids (i.e., compounds that do not occur in nature butthat can be incorporated into a polypeptide chain) and/or amino acidanalogs as are known in the art may alternatively be employed. Also, oneor more of the amino acids in a protein may be modified, for example, bythe addition of a chemical entity such as a carbohydrate group, ahydroxyl group, a phosphate group, a farnesyl group, an isofarnesylgroup, a fatty acid group, a linker for conjugation orfunctionalization, or other modification. A protein may also be a singlemolecule or may be a multi-molecular complex. A protein may be afragment of a naturally occurring protein or peptide. A protein may benaturally occurring, recombinant, synthetic, or any combination ofthese.

The term “gene” refers to a nucleic acid fragment that expresses aspecific protein, including regulatory sequences preceding (5′non-coding sequences) and following (3′ non-coding sequences) the codingsequence. “Native gene” refers to a gene as found in nature with its ownregulatory sequences. “Chimeric gene” or “chimeric construct” refers toany gene or a construct, not a native gene, comprising regulatory andcoding sequences that are not found together in nature. Accordingly, achimeric gene or chimeric construct may comprise regulatory sequencesand coding sequences that are derived from different sources, orregulatory sequences and coding sequences derived from the same source,but arranged in a manner different than that found in nature.“Endogenous gene” refers to a native gene in its natural location in thegenome of an organism. A “foreign” gene refers to a gene not normallyfound in the host organism, but which is introduced into the hostorganism by gene transfer. Foreign genes can comprise native genesinserted into a non-native organism, or chimeric genes. A “transgene” isa gene that has been introduced into the genome by a transformationprocedure.

The term “histone” refers to highly alkaline proteins found ineukaryotic cell nuclei that package and order DNA into structural unitscalled nucleosomes. They are the chief protein components of chromatin,acting as spools around which DNA winds, and play a role in generegulation. In certain embodiments, the histone is histone H1 (e.g.,histone H1F, histone H1H1). In certain embodiments, the histone ishistone H2A (e.g., histone H2AF, histone H2A1, histone H2A2). In certainembodiments, the histone is histone H2B (e.g., histone H2BF, histoneH2B1, histone H2B2). In certain embodiments, the histone is histone H3(e.g., histone H3A1, histone H3A2, histone H3A3). In certainembodiments, the histone is histone H4 (e.g., histone H41, histone H44).

The term “bromodomain” refers to a protein domain that recognizesacetylated lysine residues such as those on the N-terminal tails ofhistones. In certain embodiments, a bromodomain of a BET proteincomprises about 110 amino acids and shares a conserved fold comprising aleft-handed bundle of four alpha helices linked by diverse loop regionsthat interact with chromatin. In certain embodiments, the bromodomain isASH1L (GenBank ID: gi|8922081), ATAD2 (GenBank ID: gi|24497618), BAZ2B(GenBank ID: gi|7304923), BRD1 (GenBank ID: gi|11321642), BRD2(1)(GenBank ID: gi|4826806), BRD2(2) (GenBank ID: gi|4826806), BRD3(1)(GenBank ID: gi|11067749), BRD3(2) (GenBank ID: gi|11067749), BRD4(1)(GenBank ID: gi|19718731), BRD4(2) (GenBank ID: gi|19718731), BRD9(GenBank ID: gi|57770383), BRDT(1) (GenBank ID: gi|46399198), BRPF1(GenBank ID: gi|51173720), CECR2 (GenBank ID: gi|148612882), CREBBP(GenBank ID: gi|4758056), EP300 (GenBank ID: gi|50345997), FALZ (GenBankID: gi|38788274), GCN5L2 (GenBank ID: gi|10835101), KIAA1240 (GenBankID: gi|51460532), LOC93349 (GenBank ID: gi|134133279), PB1(1) (GenBankID: gi|30794372), PB1(2) (GenBank ID: gi|30794372), PB1(3) (GenBank ID:gi|30794372), PB1(5) (GenBank ID: gi|30794372), PB1(6) (GenBank ID:gi|30794372), PCAF (GenBank ID: gi|40805843), PHIP(2) (GenBank ID:gi|34996489), SMARCA2 (GenBank ID: gi|48255900), SMARCA4 (GenBank ID:gi|21071056), SP140 (GenBank ID: gi|52487219), TAF1(1) (GenBank ID:gi|20357585), TAF1(2) (GenBank ID: gi|20357585), TAF1L(1) (GenBank ID:gi|24429572), TAF1L(2) (GenBank ID: gi|24429572), TIF1 (GenBank ID:gi|14971415), TRIM28 (GenBank ID: gi|5032179), or WDR9(2) (GenBank ID:gi|16445436).

The term “bromodomain-containing protein” or “bromodomain protein”refers to a protein, whether wild-type or mutant, natural or synthetic,truncated or complete, or a variant thereof, that possesses the minimumamino acid sequence sufficient for a functional bromodomain capable ofmediating molecular recognition of acetylated lysine residues on asecond protein (e.g., a histone), such as on the tails of histones.Bromodomain-containing proteins include, for example, fusion proteinscomprising a bromodomain and an additional portion having a desiredfunctionality (e.g., a reporter portion).

The term “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refer tothe ability of a compound to reduce, slow, halt or prevent activity of aparticular biological process (e.g., activity of a bromodomain and/or abromodomain-containing protein) in a cell relative to vehicle.

When a compound, pharmaceutical composition, method, use, or kit isreferred to as “selectively,” “specifically,” or “competitively” bindinga first protein or a first chromatin, the compound, pharmaceuticalcomposition, method, use, or kit binds the first protein or the firstchromatin with a higher binding affinity (e.g., not less than about2-fold, not less than about 5-fold, not less than about 10-fold, notless than about 30-fold, not less than about 100-fold, not less thanabout 1,000-fold, or not less than about 10,000-fold) than binding asecond protein or second chromatin that is different from the firstprotein and the first chromatin. When a compound, pharmaceuticalcomposition, method, use, or kit is referred to as “selectively,”“specifically,” or “competitively” modulating (e.g., increasing orinhibiting) the activity of a bromodomain-containing protein, thecompound, pharmaceutical composition, method, use, or kit modulates theactivity of the bromodomain-containing protein to a greater extent(e.g., not less than about 2-fold, not less than about 5-fold, not lessthan about 10-fold, not less than about 30-fold, not less than about100-fold, not less than about 1,000-fold, or not less than about10,000-fold) than the activity of at least one protein that is differentfrom the bromodomain-containing protein.

The term “aberrant activity” refers to activity deviating from normalactivity. The term “increased activity” refers to activity higher thannormal activity.

The terms “composition” and “formulation” are used interchangeably.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)) or non-human animal. In certainembodiments, the non-human animal is a mammal (e.g., primate (e.g.,cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g.,cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.,commercially relevant bird, such as chicken, duck, goose, or turkey)).In certain embodiments, the non-human animal is a fish, reptile, oramphibian. The non-human animal may be a male or female at any stage ofdevelopment. The non-human animal may be a transgenic animal orgenetically engineered animal. A “patient” refers to a human subject inneed of treatment of a disease. The subject may also be a plant. Incertain embodiments, the plant is a land plant. In certain embodiments,the plant is a non-vascular land plant. In certain embodiments, theplant is a vascular land plant. In certain embodiments, the plant is aseed plant. In certain embodiments, the plant is a cultivated plant. Incertain embodiments, the plant is a dicot. In certain embodiments, theplant is a monocot. In certain embodiments, the plant is a floweringplant. In some embodiments, the plant is a cereal plant, e.g., maize,corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, theplant is a legume, e.g., a bean plant, e.g., soybean plant. In someembodiments, the plant is a tree or shrub.

The terms “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a compound described herein, or a composition thereof, in oron a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen). Treatment may also be continued aftersymptoms have resolved, for example, to delay and/or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. In certainembodiments, an effective amount is a therapeutically effective amount.In certain embodiments, an effective amount is a prophylacticallyeffective treatment. In certain embodiments, an effective amount is theamount of a compound or pharmaceutical composition described herein in asingle dose. In certain embodiments, an effective amount is the combinedamounts of a compound or pharmaceutical composition described herein inmultiple doses.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, pathological angiogenesis, inflammatorydiseases, and autoimmune diseases.

The term “angiogenesis” refers to the physiological process throughwhich new blood vessels form from pre-existing vessels. Angiogenesis isdistinct from vasculogenesis, which is the de novo formation ofendothelial cells from mesoderm cell precursors. The first vessels in adeveloping embryo form through vasculogenesis, after which angiogenesisis responsible for most blood vessel growth during normal or abnormaldevelopment. Angiogenesis is a vital process in growth and development,as well as in wound healing and in the formation of granulation tissue.However, angiogenesis is also a fundamental step in the transition oftumors from a benign state to a malignant one, leading to the use ofangiogenesis inhibitors in the treatment of cancer. Angiogenesis may bechemically stimulated by angiogenic proteins, such as growth factors(e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g.,excessive or insufficient) angiogenesis that amounts to and/or isassociated with a disease.

The terms “neoplasm” and “tumor” are used interchangeably and refer toan abnormal mass of tissue wherein the growth of the mass surpasses andis not coordinated with the growth of a normal tissue. A neoplasm ortumor may be “benign” or “malignant,” depending on the followingcharacteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites. The term “metastasis,” “metastatic,” or“metastasize” refers to the spread or migration of cancerous cells froma primary or original tumor to another organ or tissue and is typicallyidentifiable by the presence of a “secondary tumor” or “secondary cellmass” of the tissue type of the primary or original tumor and not ofthat of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone issaid to be metastasized prostate cancer and includes cancerous prostatecancer cells growing in bone tissue.

The term “cancer” refers to a malignant neoplasm (Stedman's MedicalDictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia,1990). Exemplary cancers include, but are not limited to, acousticneuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma(e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma);appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g.,cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinomaof the breast, papillary carcinoma of the breast, mammary cancer,medullary carcinoma of the breast); brain cancer (e.g., meningioma,glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma),medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer(e.g., cervical adenocarcinoma); choriocarcinoma; chordoma;craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer,colorectal adenocarcinoma); connective tissue cancer; epithelialcarcinoma; ependymoma: endotheliosarcoma (e.g., Kaposi's sarcoma,multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g.,uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing'ssarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease);hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastictumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastomaa.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g.,hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g.,bronchogenic carcinoma, small cell lung cancer (SCLC), non-small celllung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS);mastocytosis (e.g., systemic mastocytosis); muscle cancer;myelodysplastic syndrome (MDS); mesothelioma; myeloproliferativedisorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES));neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreaticneuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarianembryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductalpapillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer(e.g., Paget's disease of the penis and scrotum); pinealoma; primitiveneuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplasticsyndromes; intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

The term “inflammatory disease” refers to a disease caused by, resultingfrom, or resulting in inflammation. The term “inflammatory disease” mayalso refer to a dysregulated inflammatory reaction that causes anexaggerated response by macrophages, granulocytes, and/or T-lymphocytesleading to abnormal tissue damage and/or cell death. An inflammatorydisease can be either an acute or chronic inflammatory condition and canresult from infections or non-infectious causes. Inflammatory diseasesinclude, without limitation, atherosclerosis, arteriosclerosis,autoimmune disorders, multiple sclerosis, systemic lupus erythematosus,polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis,tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis,rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giantcell arteritis, progressive systemic sclerosis (scleroderma), ankylosingspondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid,diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis,Graves' disease, Goodpasture's disease, mixed connective tissue disease,sclerosing cholangitis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, pernicious anemia, inflammatory dermatoses, usualinterstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis,berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamativeinterstitial pneumonia, lymphoid interstitial pneumonia, giant cellinterstitial pneumonia, cellular interstitial pneumonia, extrinsicallergic alveolitis, Wegener's granulomatosis and related forms ofangiitis (temporal arteritis and polyarteritis nodosa), inflammatorydermatoses, delayed-type hypersensitivity reactions (e.g., poison ivydermatitis), pneumonia, respiratory tract inflammation, AdultRespiratory Distress Syndrome (ARDS), encephalitis, immediatehypersensitivity reactions, asthma, hayfever, allergies, acuteanaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury),reperfusion injury, allograft rejection, host-versus-graft rejection,appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis,cervicitis, cholangitis, chorioamnionitis, conjunctivitis,dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis,myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis,urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis,vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, opticneuritis, temporal arteritis, transverse myelitis, necrotizingfasciitis, and necrotizing enterocolitis. An ocular inflammatory diseaseincludes, but is not limited to, post-surgical inflammation.

An “autoimmune disease” refers to a disease arising from aninappropriate immune response of the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppression, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodpasture's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid, arthritis. psoriatic arthritis,systemic lupus erythematosis, psoriasis, ulcerative colitis, systemicsclerosis, dermatomyositis/polymyositis, anti-phospholipid antibodysyndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis(e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis,Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosingspondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto'sthyroiditis, and cardiomyopathy.

The term “neurological disease” refers to any disease of the nervoussystem, including diseases that involve the central nervous system(brain, brainstem and cerebellum), the peripheral nervous system(including cranial nerves), and the autonomic nervous system (parts ofwhich are located in both central and peripheral nervous system).Neurodegenerative diseases refer to a type of neurological diseasemarked by the loss of nerve cells, including, but not limited to,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,tauopathies (including frontotemporal dementia), and Huntington'sdisease. Examples of neurological diseases include, but are not limitedto, headache, stupor and coma, dementia, seizure, sleep disorders,trauma, infections, neoplasms, neuro-ophthalmology, movement disorders,demyelinating diseases, spinal cord disorders, and disorders ofperipheral nerves, muscle and neuromuscular junctions. Addiction andmental illness, include, but are not limited to, bipolar disorder andschizophrenia, are also included in the definition of neurologicaldiseases. Further examples of neurological diseases include acquiredepileptiform aphasia; acute disseminated encephalomyelitis;adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardisyndrome; Alexander disease; Alpers' disease; alternating hemiplegia;Alzheimer's disease; amyotrophic lateral sclerosis; anencephaly;Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoidcysts; arachnoiditis; Arnold-Chiari malformation; arteriovenousmalformation; Asperger syndrome; ataxia telangiectasia; attentiondeficit hyperactivity disorder; autism; autonomic dysfunction; backpain; Batten disease; Behcet's disease; Bell's palsy; benign essentialblepharospasm; benign focal; amyotrophy; benign intracranialhypertension; Binswanger's disease; blepharospasm; Bloch Sulzbergersyndrome; brachial plexus injury; brain abscess; bbrain injury; braintumors (including glioblastoma multiforme); spinal tumor; Brown-Sequardsyndrome; Canavan disease; carpal tunnel syndrome (CTS): causalgia;central pain syndrome; central pontine myelinolysis; cephalic disorder;cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebralgigantism; cerebral palsy; Charcot-Marie-Tooth disease;chemotherapy-induced neuropathy and neuropathic pain; Chiarimalformation; chorea; chronic inflammatory demyelinating polyneuropathy(CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowrysyndrome; coma, including persistent vegetative state; congenital facialdiplegia; corticobasal degeneration; cranial arteritis;craniosynostosis; Creutzfeldt-Jakob disease; cumulative traumadisorders; Cushing's syndrome; cytomegalic inclusion body disease(CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome;Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy;diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; earlyinfantile epileptic encephalopathy; empty sella syndrome; encephalitis;encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy;essential tremor; Fabry's disease; Fahr's syndrome; fainting; familialspastic paralysis; febrile seizures; Fisher syndrome; Friedreich'sataxia; frontotemporal dementia and other “tauopathies”; Gaucher'sdisease; Gerstmann's syndrome; giant cell arteritis; giant cellinclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome;HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury;headache; hemifacial spasm; hereditary spastic paraplegia; heredopathiaatactica polyneuritiformis; herpes zoster oticus; herpes zoster;Hirayama syndrome; HIV-associated dementia and neuropathy (see alsoneurological manifestations of AIDS); holoprosencephaly; Huntington'sdisease and other polyglutamine repeat diseases; hydranencephaly;hydrocephalus; hypercortisolism; hypoxia; immune-mediatedencephalomyelitis; inclusion body myositis; incontinentia pigmenti;infantile; phytanic acid storage disease; Infantile Refsum disease;infantile spasms; inflammatory myopathy; intracranial cyst; intracranialhypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease;Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease;Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eatonmyasthenic syndrome; Landau-Kleffner syndrome; lateral medullary(Wallenberg) syndrome; learning disabilities; Leigh's disease;Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy bodydementia; lissencephaly; locked-in syndrome; Lou Gehrig's disease (akamotor neuron disease or amyotrophic lateral sclerosis); lumbar discdisease; lyme disease-neurological sequelae; Machado-Joseph disease;macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieresdisease; meningitis; Menkes disease; metachromatic leukodystrophy;microcephaly; migraine; Miller Fisher syndrome; mini-strokes;mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motorneurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarctdementia; multifocal motor neuropathy; multiple sclerosis and otherdemyelinating disorders; multiple system atrophy with posturalhypotension; muscular dystrophy; myasthenia gravis; myelinoclasticdiffuse sclerosis; myoclonic encephalopathy of infants; myoclonus;myopathy; myotonia congenital; narcolepsy; neurofibromatosis;neuroleptic malignant syndrome; neurological manifestations of AIDS;neurological sequelae of lupus; neuromyotonia; neuronal ceroidlipofuscinosis; neuronal migration disorders; Niemann-Pick disease;O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinaldysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy;opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overusesyndrome; paresthesia; Parkinson's disease; paramyotonia congenita;paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome;Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy;painful neuropathy and neuropathic pain; persistent vegetative state;pervasive developmental disorders; photic sneeze reflex; phytanic acidstorage disease; Pick's disease; pinched nerve; pituitary tumors;polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia(PHN); postinfectious encephalomyelitis; postural hypotension;Prader-Willi syndrome; primary lateral sclerosis; prion diseases;progressive; hemifacial atrophy; progressive multifocalleukoencephalopathy; progressive sclerosing poliodystrophy; progressivesupranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type Iand Type II); Rasmussen's Encephalitis; reflex sympathetic dystrophysyndrome; Refsum disease; repetitive motion disorders; repetitive stressinjuries; restless legs syndrome; retrovirus-associated myelopathy; Rettsyndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease;Schilder's disease; schizencephaly; septo-optic dysplasia; shaken babysyndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleepapnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury;spinal cord tumors; spinal muscular atrophy; stiff-person syndrome;stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis;subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy;sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachsdisease; temporal arteritis; tethered spinal cord syndrome; Thomsendisease; thoracic outlet syndrome; tic douloureux; Todd's paralysis;Tourette syndrome; transient ischemic attack; transmissible spongiformencephalopathies; transverse myelitis; traumatic brain injury; tremor;trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis;vascular dementia (multi-infarct dementia); vasculitis includingtemporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg'ssyndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williamssyndrome; Wilson's disease; and Zellweger syndrome.

The term “metabolic disorder” refers to any disorder that involves analteration in the normal metabolism of carbohydrates, lipids, proteins,nucleic acids, or a combination thereof. A metabolic disorder isassociated with either a deficiency or excess in a metabolic pathwayresulting in an imbalance in metabolism of nucleic acids, proteins,lipids, and/or carbohydrates. Factors affecting metabolism include, andare not limited to, the endocrine (hormonal) control system (e.g., theinsulin pathway, the enteroendocrine hormones including GLP-1, PYY orthe like), the neural control system (e.g., GLP-1 in the brain), or thelike. Examples of metabolic disorders include, but are not limited to,diabetes (e.g., Type I diabetes, Type II diabetes, gestationaldiabetes), hyperglycemia, hyperinsulinemia, insulin resistance, andobesity.

A “kinase” is a type of enzyme that transfers phosphate groups from highenergy donor molecules, such as ATP, to specific substrates, referred toas phosphorylation. Kinases are part of the larger family ofphosphotransferases. One of the largest groups of kinases are proteinkinases, which act on and modify the activity of specific proteins.Kinases are used extensively to transmit signals and control complexprocesses in cells. Various other kinases act on small molecules such aslipids, carbohydrates, amino acids, and nucleotides, either forsignaling or to prime them for metabolic pathways. Kinases are oftennamed after their substrates. More than 500 different protein kinaseshave been identified in humans. These exemplary human protein kinasesinclude, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1,AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa,ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC,AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B,BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a,CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1,CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3,CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps, CDK9,CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2, CHK2ps1,CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e, CK1g1,CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1, CLIK1L, CLK1,CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7, CSK, CTK, CYGD, CYGF,DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1,DMPK2, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EGFR, EphA1,EphA10, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2,EphB3, EphB4, EphB6, Erk1, Erk2, Erk3, Erk3ps1, Erk3ps2, Erk3ps3,Erk3ps4, Erk4, Erk5, Erk7, FAK, FER, FERps, FES, FGFR1, FGFR2, FGFR3,FGFR4, FGR, FLT1, FLT1ps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK,GCN2, GCN22, GPRK4, GPRK5, GPRK6, GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin,HCK, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, HH498, HIPK1, HIPK2, HIPK3,HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb, IKKe, ILK,INSR, IRAK1, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK12,JAK2, JAK22, JAK3, JAK32, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT,KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1,LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP2K1,MAP2K1ps, MAP2K2, MAP2K2ps, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7,MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8,MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKps1, MARK1, MARK2, MARK3, MARK4,MARKps01, MARKps02, MARKps03, MARKps04, MARKps05, MARKps07, MARKps08,MARKps09, MARKps10, MARKps11, MARKps12, MARKps13, MARKps15, MARKps16,MARKps17, MARKps18, MARKps19, MARKps20, MARKps21, MARKps22, MARKps23,MARKps24, MARKps25, MARKps26, MARKps27, MARKps28, MARKps29, MARKps30,MAST1, MAST2, MAST3, MAST4, MASTL, MELK, MER, MET, MISR2, MLK1, MLK2,MLK3, MLK4, MLKL, MNK1, MNK1ps, MNK2, MOK, MOS, MPSK1, MPSK1ps, MRCKa,MRCKb, MRCKps, MSK1, MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3,MST3ps, MST4, MUSK, MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11,NEK2, NEK2ps1, NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7,NEK8, NEK9, NIK, NIM1, NLK, NRBP1, NRBP2, NuaK1, NuaK2, Obscn, Obscn2,OSR1, p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2,PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1,PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2,PHKg1, PHKg1ps1, PHKg1ps2, PHKg1ps3, PHKg2, PIK3R4, PIM1, PIM2, PIM3,PINK1, PITSLRE, PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh,PKCi, PKCips, PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2,PKN3, PKR, PLK1, PLK1ps1, PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY,PRP4, PRP4ps, PRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps,RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2,ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2,RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps,SgK069, SgK071, SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288,SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496,SIK, skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1,SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1,STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1,TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2, TLK2ps1, TLK2ps2,TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2,TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2,TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2,VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2, Wnk3,Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1/HGK,ZC2/TNIK, ZC3/MINK, ZC4/NRK.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

Recently, compounds have been reported to be bromodomain binding agents,e.g., international PCT publications WO 2012/075383, WO 2011/054553, WO2011/054841, WO 2011/054844, WO 2011/054845, WO 2011/054846, WO2011/054848, WO 2011/143669, and WO 2011/161031. Moreover, Japanesepatent application publication JP 2008/156311 discloses a benzimidazolederivative that is a BRD2 bromodomain binding agent and has been founduseful in treating viral infections and inhibiting viral replication.International PCT publication WO 2009/084693 discloses a series ofthienotriazolodiazepine derivatives that inhibit the binding between anacetylated histone and a bromodomain-containing protein which are usefulas anti-cancer agents. International PCT publication WO 2011/054843suggests compounds which inhibit the binding of a bromodomain with itscognate acetylated proteins may be useful in the treatment of autoimmuneand inflammatory diseases. However, there remains a need for additionalpotent and safe bromodomain binders.

The present disclosure provides compounds of Formula (I), which bindbromodomains and/or bromodomain-containing proteins. The compoundsdescribed herein may be able to bind in a pocket of a bromodomain (e.g.,a bromodomain of a bromodomain-containing protein). Without wishing tobe bound by any particular theory, the compounds described herein maybind in the pocket of a bromodomain by mimicking the contact between anacetylated lysine residue of a second protein (e.g., a histone) and thebinding pocket. In certain embodiments, the compounds described hereinbind in the pocket of the bromodomain. The compound described herein mayalso modulate (e.g., inhibit) the activity of a bromodomain and/orbromodomain-containing protein. Also provided in the present disclosureare pharmaceutical compositions, methods, uses, and kits useful inmodulating (e.g., inhibiting) the activity of a bromodomain-containingprotein (e.g., a transcription factor). The compounds, pharmaceuticalcompositions, methods, uses, and kits may be useful in treating and/orpreventing diseases associated with a bromodomain, diseases associatedwith a bromodomain-containing protein, diseases associated with theactivity (e.g., aberrant activity) of a bromodomain, and diseasesassociated with the activity (e.g., aberrant activity) of abromodomain-containing protein. Exemplary diseases that may be preventedand/or treated with compounds described herein include proliferativediseases (e.g., cancers, benign neoplasms, pathological angiogenesis,inflammatory diseases, and autoimmune diseases), autoimmune diseases,cardiovascular diseases, viral infections, fibrotic diseases,neurological diseases, metabolic diseases, endocrine diseases, andradiation poisoning. The compounds, pharmaceutical compositions,methods, uses, and kits may also be useful for male contraception andfor preventing and/or treating a viral infection (e.g., by inhibitingthe replication of a virus, by killing a virus).

Compounds

The present invention provides compounds of Formula (I):

or pharmaceutically acceptable salt thereof; wherein:

-   -   R^(A) is hydrogen, substituted or unsubstituted acyl,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, or substituted        or unsubstituted heteroaryl;    -   R^(B) is hydrogen, substituted or unsubstituted acyl,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, or substituted        or unsubstituted heteroaryl;    -   or R^(A) and R^(B) are joined to form a substituted or        unsubstituted, carbocyclic ring, or a substituted or        unsubstituted, heterocyclic ring;    -   R^(C) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or a        nitrogen protecting group;    -   R¹ is hydrogen, halogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² and R³ are each independently hydrogen, substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, —C(═O)R^(D1), —C(═O)OR^(D1),        —C(═O)N(R^(D1))₂, or a nitrogen protecting group, wherein each        instance of R^(D1) is independently hydrogen, substituted or        unsubstituted acyl, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, a        nitrogen protecting group when attached to a nitrogen atom, or        an oxygen protecting group when attached to an oxygen atom, or        two R^(D1) groups are joined to form a substituted or        unsubstituted heterocyclic or substituted or unsubstituted        heteroaryl ring, or a nitrogen protecting group when attached to        a nitrogen atom;    -   each instance of R^(B1) is independently hydrogen, halogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, —OR^(B1a), —N(R^(B1a))₂, —SR^(B1a),        —CN, —SCN, —C(═NR^(B1a))R^(B1a), —C(═NR^(B1a))OR^(B1a),        —C(═NR^(B1a))N(R^(B1a))₂, —C(═O)R^(B1a), —C(═O)OR^(B1a),        —C(═O)N(R^(B1a))₂, —NO₂, —NR^(B1a)C(═O)R^(B1a),        —NR^(B1a)C(═O)OR^(B1a), —NR^(B1a)C(═O)N(R^(B1a))₂,        —OC(═O)R^(B1a), —OC(═O)OR^(B1a), or —OC(═O)N(R^(B1a))₂, wherein        each instance of R^(B1a) is independently hydrogen, substituted        or unsubstituted acyl, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, a        nitrogen protecting group when attached to a nitrogen atom, an        oxygen protecting group when attached to an oxygen atom, or a        sulfur protecting group when attached to a sulfur atom, or two        R^(B1a) groups are joined to form a substituted or unsubstituted        heterocyclic or substituted or unsubstituted heteroaryl ring;    -   R^(B3) is hydrogen, halogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —OR^(B3a), —N(R^(B3a))₂, —SR^(B3a), —CN, —SCN,        —C(═NR^(B3a))R^(B3a), —C(═NR^(B3a))OR^(B3a),        —C(═NR^(B3a))N(R^(B3a))₂, —C(═O)R^(B3a), —C(═O)OR^(B3a),        —C(═O)N(R^(B3a))₂, —NO₂, —NR^(B3a)C(═O)R^(B3a),        —NR^(B3a)C(═O)OR^(B3a), —NR^(B3a)C(═O)N(R^(B3a))₂,        —OC(═O)R^(B3a), —OC(═O)OR^(B3a), or —OC(═O)N(R^(B3a))₂, wherein        each instance of R^(B3a) is independently hydrogen, substituted        or unsubstituted acyl, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, a        nitrogen protecting group when attached to a nitrogen atom, an        oxygen protecting group when attached to an oxygen atom, or a        sulfur protecting group when attached to a sulfur atom, or two        R^(R3a) groups are joined to form a substituted or unsubstituted        heterocyclic or substituted or unsubstituted heteroaryl ring;    -   p is 0 or an integer between 1 and 4, inclusive;    -   L is a bond,

-   -   R^(a1) is hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, or        a nitrogen protecting group; and    -   each instance of R^(c1) is independently hydrogen, halogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, —OR^(c1a), —N(R^(c1a))₂, —SR^(c1a),        —CN, —C(═O)R^(c1a), —C(═O)OR^(c1a), —C(═O)N(R^(c1a))₂,        —NR^(c1a)C(═O)R^(c1a), —NR^(c1a)C(═O)OR^(c1a),        —NR^(c1a)C(═O)N(R^(c1a))₂, —OC(═O)R^(c1a), or        —OC(═O)N(R^(c1a))₂, wherein each instance of R^(c1a) is        independently hydrogen, substituted or unsubstituted acyl,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, a nitrogen protecting group when        attached to a nitrogen atom, an oxygen protecting group when        attached to an oxygen atom, or a sulfur protecting group when        attached to a sulfur atom, or two R^(c1a) groups are joined to        form a substituted or unsubstituted heterocyclic or substituted        or unsubstituted heteroaryl ring.

In certain embodiments, the present invention provides compounds ofFormula (Ia):

In certain embodiments, the present invention provides compounds ofFormula (Ib):

In certain embodiments, the present invention provides compounds ofFormula (I) and pharmaceutically acceptable salts thereof.Groups R^(A), R^(A2), R^(B), R^(B2), and R^(C)

Formula (I) includes substituent R^(A) on the hydrazide moiety. Incertain embodiments, R^(A) is H. In certain embodiments, R^(A) issubstituted acyl. In certain embodiments, R^(A) is unsubstituted acyl.In certain embodiments, R^(A) is acetyl. In certain embodiments, R^(A)is —C(═O)R^(A2) (e.g., —C(═O) (substituted or unsubstituted alkyl)). Incertain embodiments, R^(A) is —C(═O)OR^(A2) (e.g., —C(═O)O (substitutedor unsubstituted alkyl) or —C(═O)OH). In certain embodiments, R^(A) is—C(═O)N(R^(A2))₂, (e.g., —C(═O)NH₂, —C(═O)NH (substituted orunsubstituted alkyl), or —C(═O)N (substituted or unsubstituted alkyl)₂).In certain embodiments, R^(A) is unsubstituted alkyl. In certainembodiments, R^(A) is substituted alkyl. In certain embodiments, R^(A)is unsubstituted C₁₋₁₂ alkyl. In certain embodiments, R^(A) issubstituted C₁₋₁₂ alkyl. In certain embodiments, R^(A) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(A) is substituted C₁₋₆ alkyl. Incertain embodiments, R^(A) is C₁₋₆ alkyl substituted with at least onehalogen. In certain embodiments, R^(A) is —CH₃. In certain embodiments,R^(A) is substituted methyl. In certain embodiments, R^(A) is —CH₂F,—CHF₂, or —CF₃. In certain embodiments, R^(A) is ethyl. In certainembodiments, R^(A) is propyl. In certain embodiments, R^(A) is butyl. Incertain embodiments, R^(A) is pentyl. In certain embodiments, R^(A) ishexyl. In certain embodiments, R^(A) is unsubstituted alkenyl. Incertain embodiments, R^(A) is substituted alkenyl. In certainembodiments, R^(A) is unsubstituted C₁₋₁₂ alkenyl. In certainembodiments, R^(A) is substituted C₁₋₁₂ alkenyl. In certain embodiments,R^(A) is unsubstituted C₁₋₆ alkenyl. In certain embodiments, R^(A) issubstituted C₁₋₆ alkenyl. In certain embodiments, R^(A) is unsubstitutedalkynyl. In certain embodiments, R^(A) is substituted alkynyl. Incertain embodiments, R^(A) is unsubstituted C₁₋₁₂ alkynyl. In certainembodiments, R^(A) is substituted C₁₋₁₂ alkynyl. In certain embodiments,R^(A) is unsubstituted C₁₋₆ alkynyl. In certain embodiments, R^(A) issubstituted C₁₋₆ alkynyl. In certain embodiments, R^(A) is substitutedcarbocyclyl. In certain embodiments, R^(A) is unsubstituted carbocyclyl.In certain embodiments, R^(A) is saturated carbocyclyl. In certainembodiments, R^(A) is unsaturated carbocyclyl. In certain embodiments,R^(A) is 3- to 8-membered, monocyclic carbocyclyl, optionally including1, 2, or 3 double bonds in the carbocyclic ring system. In certainembodiments, R^(A) is 5- to 14-membered, bicyclic carbocyclyl,optionally including 1, 2, 3, or 4 double bonds in the carbocyclic ringsystem. In certain embodiments, R^(A) is 5- to 20-membered, tricycliccarbocyclyl, optionally including 1, 2, 3, 4, or 5 double bonds in thecarbocyclic ring system. In certain embodiments, R^(A) is 5- to26-membered, tetracyclic carbocyclyl, optionally including 1, 2, 3, 4,5, or 6 double bonds in the carbocyclic ring system. In certainembodiments, R^(A) is substituted heterocyclyl. In certain embodiments,R^(A) is unsubstituted heterocyclyl. In certain embodiments, R^(A) issaturated heterocyclyl. In certain embodiments, R^(A) is unsaturatedheterocyclyl. In certain embodiments, R^(A) is 3- to 8-membered,monocyclic heterocyclyl, optionally including 1 or 2 double bonds in theheterocyclic ring system, wherein 1, 2, or 3 atoms in the heterocyclicring system are independently nitrogen, oxygen, or sulfur. In certainembodiments, R^(A) is 5- to 14-membered, bicyclic heterocyclyl,optionally including 1, 2, or 3 double bonds in the heterocyclic ringsystem, wherein 1, 2, 3, or 4 atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur. In certain embodiments, R^(A)is 5- to 20-membered, tricyclic heterocyclyl, optionally including 1, 2,3, or 4 double bonds in the heterocyclic ring system, wherein 1, 2, 3,4, or 5 atoms in the heterocyclic ring system are independentlynitrogen, oxygen, or sulfur. In certain embodiments, R^(A) issubstituted aryl. In certain embodiments, R^(A) is unsubstituted aryl.In certain embodiments, R^(A) is 6- to 14-membered aryl. In certainembodiments, R^(A) is 6- to 10-membered aryl. In certain embodiments,R^(A) is substituted phenyl. In certain embodiments, R^(A) isunsubstituted phenyl. In certain embodiments, R^(A) is substitutednaphthyl. In certain embodiments, R^(A) is unsubstituted naphthyl. Incertain embodiments, R^(A) is substituted heteroaryl. In certainembodiments, R^(A) is unsubstituted heteroaryl. In certain embodiments,R^(A) is 5- to 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4atoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur. In certain embodiments, R^(A) is 8- to 10-membered, bicyclicheteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring systemare independently nitrogen, oxygen, or sulfur. In certain embodiments,R^(A) is a moiety in Table A. In certain embodiments, R^(A) is a moietyin Table B. An R^(A) group may independently include one or moresubstituents R^(A2). In certain embodiments, all instances of R^(A2) arethe same. In certain embodiments, two instances of R^(A2) are differentfrom each other. In certain embodiments, at least one instance of R^(A2)is H. In certain embodiments, each instance of R^(A2) is H. In certainembodiments, at least one instance of R^(A2) is substituted orunsubstituted acyl (e.g., acetyl). In certain embodiments, at least oneinstance of R^(A2) is substituted or unsubstituted alkyl (e.g.,substituted or unsubstituted C₁₋₆ alkyl). In certain embodiments, atleast one instance of R^(A2) is —CH₃. In certain embodiments, at leastone instance of R^(A2) is —CF₃, unsubstituted ethyl, perfluoroethyl,unsubstituted propyl, perfluoropropyl, unsubstituted butyl, orperfluorobutyl. In certain embodiments, at least one instance of R^(A2)is substituted or unsubstituted alkenyl (e.g., substituted orunsubstituted C₁₋₆ alkenyl). In certain embodiments, at least oneinstance of R^(A2) is substituted or unsubstituted alkynyl (e.g.,substituted or unsubstituted C₁₋₆ alkynyl). In certain embodiments, atleast one instance of R^(A2) is substituted or unsubstituted carbocyclyl(e.g., substituted or unsubstituted, 3- to 8-membered, monocycliccarbocyclyl, optionally including 1, 2, or 3 double bonds in thecarbocyclic ring system; or substituted or unsubstituted, 5- to14-membered, bicyclic carbocyclyl, optionally including 1, 2, 3, or 4double bonds in the carbocyclic ring system). In certain embodiments, atleast one instance of R^(A2) is substituted or unsubstitutedheterocyclyl (e.g., substituted or unsubstituted, 3- to 8-membered,monocyclic heterocyclyl, optionally including 1 or 2 double bonds in theheterocyclic ring system, wherein 1, 2, or 3 atoms in the heterocyclicring system are independently nitrogen, oxygen, or sulfur; orsubstituted or unsubstituted, 5- to 14-membered, bicyclic heterocyclyl,optionally including 1, 2, or 3 double bonds in the heterocyclic ringsystem, wherein 1, 2, 3, or 4 atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments, atleast one instance of R^(A2) is substituted or unsubstituted aryl (e.g.,substituted or unsubstituted, 6- to 10-membered aryl). In certainembodiments, at least one instance of R^(A2) is substituted orunsubstituted phenyl. In certain embodiments, at least one instance ofR^(A2) is substituted or unsubstituted heteroaryl (e.g., substituted orunsubstituted, 5- to 6-membered, monocyclic heteroaryl, or substitutedor unsubstituted, 8- to 10-membered, bicyclic heteroaryl, wherein 1, 2,3, or 4 atoms in the heteroaryl ring system are independently nitrogen,oxygen, or sulfur). In certain embodiments, at least one instance ofR^(A2) is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to anitrogen atom. In certain embodiments, R^(A2) is an oxygen protectinggroup (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn,allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. Incertain embodiments, R^(A2) is a sulfur protecting group (e.g.,acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl,or triphenylmethyl) when attached to a sulfur atom. In certainembodiments, two instances of R^(A2) are joined to form a substituted orunsubstituted heterocyclic ring (e.g., substituted or unsubstituted, 3-to 8-membered, monocyclic heterocyclic ring, optionally including 1 or 2double bonds in the heterocyclic ring system, wherein 1, 2, or 3 atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur). In certain embodiments, two instances of R^(A2) are joined toform a substituted or unsubstituted heteroaryl ring (e.g., substitutedor unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein1, 2, 3, or 4 atoms in the heteroaryl ring system are independentlynitrogen, oxygen, or sulfur).

Formula (I) includes substituent R^(B) on the hydrazide moiety. Incertain embodiments, R^(B) is H. In certain embodiments, R^(B) issubstituted acyl. In certain embodiments, R^(B) is unsubstituted acyl.In certain embodiments, R^(B) is acetyl. In certain embodiments, R^(B)is —C(═O)R^(a) (e.g., —C(═O) (substituted or unsubstituted alkyl)). Incertain embodiments, R^(B) is —C(═O)OR^(a) (e.g., —C(═O)O (substitutedor unsubstituted alkyl) or —C(═O)OH). In certain embodiments, R^(B) is—C(═O)N(R^(a))₂, (e.g., —C(═O)NH₂, —C(═O)NH (substituted orunsubstituted alkyl), or —C(═O)N (substituted or unsubstituted alkyl)₂).In certain embodiments, R^(B) is unsubstituted alkyl. In certainembodiments, R^(B) is substituted alkyl. In certain embodiments, R^(B)is unsubstituted C₁₋₁₂ alkyl. In certain embodiments, R^(B) issubstituted C₁₋₁₂ alkyl. In certain embodiments, R^(B) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(B) is substituted C₁₋₆ alkyl. Incertain embodiments, R^(B) is C₁₋₆ alkyl substituted with at least onehalogen. In certain embodiments, R^(B) is —CH₃. In certain embodiments,R^(B) is substituted methyl. In certain embodiments, R^(B) is —CH₂F,—CHF₂, or —CF₃. In certain embodiments, R^(B) is ethyl. In certainembodiments, R^(B) is propyl. In certain embodiments, R^(B) is butyl. Incertain embodiments, R^(B) is pentyl. In certain embodiments, R^(B) ishexyl. In certain embodiments, R^(B) is unsubstituted alkenyl. Incertain embodiments, R^(B) is substituted alkenyl. In certainembodiments, R^(B) is unsubstituted C₁₋₁₂ alkenyl. In certainembodiments, R^(B) is substituted C₁₋₁₂ alkenyl. In certain embodiments,R^(B) is unsubstituted C₁₋₆ alkenyl. In certain embodiments, R^(B) issubstituted C₁₋₆ alkenyl. In certain embodiments, R^(B) is unsubstitutedalkynyl. In certain embodiments, R^(B) is substituted alkynyl. Incertain embodiments, R^(B) is unsubstituted C₁₋₁₂ alkynyl. In certainembodiments, R^(B) is substituted C₁₋₁₂ alkynyl. In certain embodiments,R^(B) is unsubstituted C₁₋₆ alkynyl. In certain embodiments, R^(B) issubstituted C₁₋₆ alkynyl. In certain embodiments, R^(B) is substitutedcarbocyclyl. In certain embodiments, R^(B) is unsubstituted carbocyclyl.In certain embodiments, R^(B) is saturated carbocyclyl. In certainembodiments, R^(B) is unsaturated carbocyclyl. In certain embodiments,R^(B) is 3- to 8-membered, monocyclic carbocyclyl, optionally including1, 2, or 3 double bonds in the carbocyclic ring system. In certainembodiments, R^(B) is 5- to 14-membered, bicyclic carbocyclyl,optionally including 1, 2, 3, or 4 double bonds in the carbocyclic ringsystem. In certain embodiments, R^(B) is 5- to 20-membered, tricycliccarbocyclyl, optionally including 1, 2, 3, 4, or 5 double bonds in thecarbocyclic ring system. In certain embodiments, R^(B) is 5- to26-membered, tetracyclic carbocyclyl, optionally including 1, 2, 3, 4,5, or 6 double bonds in the carbocyclic ring system. In certainembodiments, R^(B) is substituted heterocyclyl. In certain embodiments,R^(B) is unsubstituted heterocyclyl. In certain embodiments, R^(B) issaturated heterocyclyl. In certain embodiments, R^(B) is unsaturatedheterocyclyl. In certain embodiments, R^(B) is 3- to 8-membered,monocyclic heterocyclyl, optionally including 1 or 2 double bonds in theheterocyclic ring system, wherein 1, 2, or 3 atoms in the heterocyclicring system are independently nitrogen, oxygen, or sulfur. In certainembodiments, R^(B) is 5- to 14-membered, bicyclic heterocyclyl,optionally including 1, 2, or 3 double bonds in the heterocyclic ringsystem, wherein 1, 2, 3, or 4 atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur. In certain embodiments, R^(B)is 5- to 20-membered, tricyclic heterocyclyl, optionally including 1, 2,3, or 4 double bonds in the heterocyclic ring system, wherein 1, 2, 3,4, or 5 atoms in the heterocyclic ring system are independentlynitrogen, oxygen, or sulfur. In certain embodiments, R^(B) issubstituted aryl. In certain embodiments, R^(B) is unsubstituted aryl.In certain embodiments, R^(B) is 6- to 14-membered aryl. In certainembodiments, R^(B) is 6- to 10-membered aryl. In certain embodiments,R^(B) is substituted phenyl. In certain embodiments, R^(B) isunsubstituted phenyl. In certain embodiments, R^(B) is substitutednaphthyl. In certain embodiments, R^(B) is unsubstituted naphthyl. Incertain embodiments, R^(B) is substituted heteroaryl. In certainembodiments, R^(B) is unsubstituted heteroaryl. In certain embodiments,R^(B) is 5- to 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4atoms in the heteroaryl ring system are independently nitrogen, oxygen,or sulfur. In certain embodiments, R^(B) is 8- to 10-membered, bicyclicheteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring systemare independently nitrogen, oxygen, or sulfur. In certain embodiments,R^(B) is a moiety in Table A. In certain embodiments, R^(B) is a moietyin Table B. An R^(B) group may independently include one or moresubstituents R^(B2). In certain embodiments, all instances of R^(B2) arethe same. In certain embodiments, two instances of R^(B2) are differentfrom each other. In certain embodiments, at least one instance of R^(B2)is H. In certain embodiments, each instance of R^(B2) is H. In certainembodiments, at least one instance of R^(B2) is substituted orunsubstituted acyl (e.g., acetyl). In certain embodiments, at least oneinstance of R^(B2) is substituted or unsubstituted alkyl (e.g.,substituted or unsubstituted C₁₋₆ alkyl). In certain embodiments, atleast one instance of R^(B2) is —CH₃. In certain embodiments, at leastone instance of R^(B2) is —CF₃, unsubstituted ethyl, perfluoroethyl,unsubstituted propyl, perfluoropropyl, unsubstituted butyl, orperfluorobutyl. In certain embodiments, at least one instance of R^(B2)is substituted or unsubstituted alkenyl (e.g., substituted orunsubstituted C₁₋₆ alkenyl). In certain embodiments, at least oneinstance of R^(B2) is substituted or unsubstituted alkynyl (e.g.,substituted or unsubstituted C₁₋₆ alkynyl). In certain embodiments, atleast one instance of R^(B2) is substituted or unsubstituted carbocyclyl(e.g., substituted or unsubstituted, 3- to 8-membered, monocycliccarbocyclyl, optionally including 1, 2, or 3 double bonds in thecarbocyclic ring system; or substituted or unsubstituted, 5- to14-membered, bicyclic carbocyclyl, optionally including 1, 2, 3, or 4double bonds in the carbocyclic ring system). In certain embodiments, atleast one instance of R^(B2) is substituted or unsubstitutedheterocyclyl (e.g., substituted or unsubstituted, 3- to 8-membered,monocyclic heterocyclyl, optionally including 1 or 2 double bonds in theheterocyclic ring system, wherein 1, 2, or 3 atoms in the heterocyclicring system are independently nitrogen, oxygen, or sulfur; orsubstituted or unsubstituted, 5- to 14-membered, bicyclic heterocyclyl,optionally including 1, 2, or 3 double bonds in the heterocyclic ringsystem, wherein 1, 2, 3, or 4 atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur). In certain embodiments, atleast one instance of R^(B2) is substituted or unsubstituted aryl (e.g.,substituted or unsubstituted, 6- to 10-membered aryl). In certainembodiments, at least one instance of R^(B2) is substituted orunsubstituted phenyl. In certain embodiments, at least one instance ofR^(B2) is substituted or unsubstituted heteroaryl (e.g., substituted orunsubstituted, 5- to 6-membered, monocyclic heteroaryl, or substitutedor unsubstituted, 8- to 10-membered, bicyclic heteroaryl, wherein 1, 2,3, or 4 atoms in the heteroaryl ring system are independently nitrogen,oxygen, or sulfur). In certain embodiments, at least one instance ofR^(B2) is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to anitrogen atom. In certain embodiments, R^(B2) is an oxygen protectinggroup (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn,allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom. Incertain embodiments, R^(B2) is a sulfur protecting group (e.g.,acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl,or triphenylmethyl) when attached to a sulfur atom. In certainembodiments, two instances of R^(B2) are joined to form a substituted orunsubstituted heterocyclic ring (e.g., substituted or unsubstituted, 3-to 8-membered, monocyclic heterocyclic ring, optionally including 1 or 2double bonds in the heterocyclic ring system, wherein 1, 2, or 3 atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur). In certain embodiments, two instances of R^(B2) are joined toform a substituted or unsubstituted heteroaryl ring (e.g., substitutedor unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein1, 2, 3, or 4 atoms in the heteroaryl ring system are independentlynitrogen, oxygen, or sulfur).

In certain embodiments, R^(A) and R^(B) are the same. In certainembodiments, R^(A) and R^(B) are different from each other. In certainembodiments, R^(A) and R^(B) are joined to form a substituted orunsubstituted, saturated or unsaturated, carbocyclic ring. In certainembodiments, R^(A) and R^(B) are joined to form a 3- to 8-membered,monocyclic carbocyclic ring, optionally including 1, 2, or 3 doublebonds in the carbocyclic ring system. In certain embodiments, R^(A) andR^(B) are joined to form a 5- to 14-membered, bicyclic carbocyclic ring,optionally including 1, 2, 3, or 4 double bonds in the carbocyclic ringsystem. In certain embodiments, R^(A) and R^(B) are joined to form a 5-to 20-membered, tricyclic carbocyclic ring, optionally including 1, 2,3, 4, or 5 double bonds in the carbocyclic ring system.

In certain embodiments, R^(A) and R^(B) are joined to form a substitutedor unsubstituted, saturated or unsaturated, heterocyclic ring. Incertain embodiments, R^(A) and R^(B) are joined to form a 3- to8-membered, monocyclic heterocyclic ring, optionally including 1 or 2double bonds in the heterocyclic ring system, wherein 1, 2, or 3 atomsin the heterocyclic ring system are independently nitrogen, oxygen, orsulfur. In certain embodiments, R^(A) and R^(B) are joined to form a 5-to 14-membered, bicyclic heterocyclic ring, optionally including 1, 2,or 3 double bonds in the heterocyclic ring system, wherein 1, 2, 3, or 4atoms in the heterocyclic ring system are independently nitrogen,oxygen, or sulfur. In certain embodiments, R^(A) and R^(B) are joined toform a 5- to 20-membered, tricyclic heterocyclic ring, optionallyincluding 1, 2, 3, 4, or 5 double bonds in the heterocyclic ring system,wherein 1, 2, 3, 4, or 5 atoms in the heterocyclic ring system areindependently nitrogen, oxygen, or sulfur. In certain embodiments, R^(A)and R^(B) are joined to form a moiety in Table C.

Formula (I) includes substituent R^(C) on a nitrogen atom. In certainembodiments, R^(C) is H. In certain embodiments, R^(C) is substituted orunsubstituted C₁₋₆ alkyl (e.g., —CH₃, —CF₃, unsubstituted ethyl,perfluoroethyl, unsubstituted propyl, perfluoropropyl, unsubstitutedbutyl, or perfluorobutyl). In certain embodiments, R^(C) is a nitrogenprotecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, acetyl, or Ts).

Groups R^(B3) and R^(B3a)

As generally defined herein, R^(B3) is hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(B3a), —N(R^(B3a))₂,—SR^(B3a), —CN, —SCN, —C(═NR^(B3a))R^(B3a), —C(═NR^(B3a))OR^(B3a),—C(═NR^(B3a))N(R^(B3a))₂, —C(═O)R^(B3a), —C(═O)OR^(B3a),—C(═O)N(R^(B3a))₂, —NO₂, —NR^(B3a)C(═O)R^(B3a), —NR^(B3a)C(═O)OR^(B3a),—NR^(B3a)C(═O)N(R^(B3))₂, —OC(═O)R^(B3a), —OC(═O)OR^(B3a), or—OC(═O)N(R^(B3a))₂. As generally defined herein, each instance ofR^(B3a) is independently hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(B3a)groups are joined to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring.

In certain embodiments, R^(B3) is hydrogen. In certain embodiments,R^(B3) is halogen (e.g., F, Cl, Br, or I). In certain embodiments,R^(B3) is —OR^(B3a); and R^(B3a) is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, R^(B3) is —N(R^(B3a))₂; and R^(B3a) issubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(B3)is —SR^(B3a); and R^(B3a) is substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(B3) is halogen (e.g., fluorine). In certainembodiments, R^(B3) is substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, R^(B3) is substituted or unsubstituted methyl. Incertain embodiments, R^(B3) is unsubstituted methyl.

Group R¹

As generally defined herein, R¹ is hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In certain embodiments, the carbon to which R¹ is attached is astereocenter of the (S)-configuration. In certain embodiments, thecarbon to which R¹ is attached is a stereocenter of the(R)-configuration. In certain embodiments, the carbon to which R¹ isattached is a mixture of stereocenters of the (R)- and(S)-configurations.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ ishalogen, e.g., fluoro, chloro, bromo, or iodo.

In certain embodiments, R¹ is substituted or unsubstituted C₁₋₆ alkyl,e.g., methyl, ethyl, propyl, or butyl. In certain embodiments, R¹ isunsubstituted methyl. In certain embodiments, R¹ is unsubstituted ethyl.In certain embodiments, R¹ is branched C₁₋₆ alkyl, e.g., isopropyl,isobutyl, or t-butyl. In certain embodiments, R¹ is substituted orunsubstituted C₁₋₆ haloalkyl, e.g., —CF₃, —CH₂CF₃, —CHF₂, —CH₂F,—CF₂CH₃, or —CF₂CF₃. In certain embodiments, R¹ is substituted orunsubstituted aralkyl, e.g., benzyl. In certain embodiments, R¹ issubstituted or unsubstituted alkoxyalkyl, e.g., —CH₂OR^(1a),—CH₂CH₂OR^(1a), or —CH₂CH(CH₃)OR^(1a), wherein R^(1a) is substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₁₋₆ haloalkyl,or substituted or unsubstituted phenyl.

In certain embodiments, R¹ is substituted or unsubstituted alkenyl,e.g., vinyl, allyl, propenyl, or butenyl. In certain embodiments, R¹ issubstituted or unsubstituted alkynyl, e.g., propargyl, propynyl, orbutynyl.

In certain embodiments, R¹ is substituted or unsubstituted carbocyclyl.In certain embodiments, R¹ is substituted or unsubstituted 3-6 memberedcarbocyclyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In certain embodiments, R¹ is 3-6 membered carbocyclyl substituted with1, 2, 3, 4, or 5 instances of R^(1b), wherein each instance of R^(1b) isindependently halogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(1ba), —N(R^(1ba))₂, —SR^(1ba), —CN, —SCN,—C(═NR^(1ba))R^(1ba), —C(═NR^(1ba))OR^(1ba), —C(═NR^(1ba))N(R^(1ba))₂,—C(═O)R^(1ba), —C(═O)OR^(1ba), —C(═O)N(R^(1ba))₂, —NO₂,—NR^(1ba)C(═O)R^(1ba), —NR^(1ba)C(═O)OR^(1ba),—NR^(1ba)C(═O)N(R^(1ba))₂, —OC(═O)R^(1ba), —OC(═O)OR^(1ba), or—OC(═O)N(R^(1ba))₂ and each instance of R^(1ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(1ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R¹ is substituted or unsubstituted heterocyclyl.In certain embodiments, R¹ is substituted or unsubstituted 3-6 memberedheterocyclyl, e.g., oxetanyl, tetrahydrofuranyl, pyranyl, azetidinyl,pyrrolidinyl, or piperidinyl. In certain embodiments, R¹ is 3-6 memberedheterocyclyl substituted with 1, 2, 3, 4, or 5 instances of R^(1b),wherein each instance of Rib is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(1ba), —N(R^(1ba))₂,—SR^(1ba), —CN, —SCN, —C(═NR^(1ba))R^(1ba), —C(═NR^(1ba))OR^(1ba),—C(═NR^(1ba))N(R^(1ba))₂, —C(═O)R^(1ba), —C(═O)OR^(1ba),—C(═O)N(R^(1ba))₂, —NO₂, —NR^(1ba)C(═O)R^(1ba), —NR^(1ba)C(═O)OR^(1ba),—NR^(1ba)C(═O)N(R^(1ba))₂, —OC(═O)R^(1ba), —OC(═O)OR^(1ba), or—OC(═O)N(R^(1ba))₂ and each instance of R^(1ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(1ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R¹ is substituted or unsubstituted aryl. Incertain embodiments, R¹ is substituted or unsubstituted phenyl. Incertain embodiments, R¹ is phenyl substituted with 1, 2, 3, 4, or 5instances of R1b, wherein each instance of Rib is independently halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(1ba), —N(R^(1ba))₂, —SR^(1ba), —CN, —SCN,—C(═NR^(1ba))R^(1ba), —C(═NR^(1ba))OR^(1ba), —C(═NR^(1ba))N(R^(1ba))₂,—C(═O)R^(1ba), —C(═O)OR^(1ba), —C(═O)N(R^(1ba))₂, —NO₂,—NR^(1ba)C(═O)R^(1ba), —NR^(1ba)C(═O)OR^(1ba),—NR^(1ba)C(═O)N(R^(1ba))₂, —OC(═O)R^(1ba), —OC(═O)OR^(1ba), or—OC(═O)N(R^(1ba))₂ and each instance of R^(1ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(1ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R¹ is substituted or unsubstituted heteroaryl.In certain embodiments, R¹ is substituted or unsubstituted 5-6 memberedheteroaryl, e.g., pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isothiazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl,or pyridizinyl. In certain embodiments, R¹ is 5-6 membered heteroarylsubstituted with 1, 2, 3, 4, or 5 instances of R^(1b), wherein eachinstance of R^(1b) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(1ba), —N(R^(1ba))₂,—SR^(1ba), —CN, —SCN, —C(═NR^(1ba))R^(1ba), —C(═NR^(1ba))OR^(1ba),—C(═NR^(1ba))N(R^(1ba))₂, —C(═O)R^(1ba), —C(═O)OR^(1ba),—C(═O)N(R^(1ba))₂, —NO₂, —NR^(1ba)C(═O)R^(1ba), —NR^(1ba)C(═O)OR^(1ba),—NR^(1ba)C(═O)N(R^(1ba))₂, —OC(═O)R^(1ba), —OC(═O)OR^(1ba), or—OC(═O)N(R^(1ba))₂ and each instance of R^(1ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(1ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

Groups R², R³, and R^(D1)

As generally defined herein, R² and R³ are each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —C(═O)R^(D1), —C(═O)OR^(D1), —C(═O)N(R^(D1))₂, or a nitrogenprotecting group. As generally defined herein, R^(D1) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, or an oxygen protecting groupwhen attached to an oxygen atom, or two R^(D1) groups are joined to forma substituted or unsubstituted heterocyclic or substituted orunsubstituted heteroaryl ring, or a nitrogen protecting group whenattached to a nitrogen atom.

In certain embodiments, R² is hydrogen. In certain embodiments, R² isnot hydrogen. In certain embodiments, R² is substituted or unsubstitutedC₁₋₆ alkyl, e.g., methyl, ethyl, propyl, or butyl. In certainembodiments, R² is unsubstituted methyl. In certain embodiments, R² isunsubstituted ethyl. In certain embodiments, R² is unsubstitutedn-propyl. In certain embodiments, R² is branched C₁₋₆ alkyl, e.g.,isopropyl, isobutyl, or t-butyl. In certain embodiments, R² isunsubstituted isopropyl. In certain embodiments, R² is unsubstitutedt-butyl. In certain embodiments, R² is substituted or unsubstituted C₁₋₆haloalkyl, e.g., —CF₃, —CH₂CF₃, —CHF₂, —CH₂F, —CF₂CH₃, or —CF₂CF₃. Incertain embodiments, R² is substituted or unsubstituted aralkyl, e.g.,benzyl. In certain embodiments, R² is substituted or unsubstitutedalkoxyalkyl, e.g., —CH₂OR^(2a), —CH₂CH₂OR^(2a), or —CH₂CH(CH₃)OR^(2a),wherein R^(2a) is substituted or unsubstituted C₁₋₆ alkyl, substitutedor unsubstituted C₁₋₆ haloalkyl, or substituted or unsubstituted phenyl.

In certain embodiments, R² is substituted or unsubstituted alkenyl,e.g., vinyl, allyl, propenyl, or butenyl. In certain embodiments, R² issubstituted or unsubstituted alkynyl, e.g., propargyl, propynyl, orbutynyl.

In certain embodiments, R² is substituted or unsubstituted carbocyclyl.In certain embodiments, R² is substituted or unsubstituted 3-6 memberedcarbocyclyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In certain embodiments, R² is unsubstituted cyclopropyl. In certainembodiments, R² is unsubstituted cyclobutyl. In certain embodiments, R²is unsubstituted cyclopentyl. In certain embodiments, R² isunsubstituted cyclohexyl. In certain embodiments, R² is 3-6 memberedcarbocyclyl substituted with 1, 2, 3, 4, or 5 instances of R^(2b),wherein each instance of R^(2b) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(2ba), —N(R^(2ba))₂,—SR^(2ba), —CN, —SCN, —C(═NR^(2ba))R^(2ba), —C(═NR^(2ba))OR^(2ba),—C(═NR^(2ba))N(R^(2ba))₂, —C(═O)R^(2ba), —C(═O)OR^(2ba),—C(═O)N(R^(2ba))₂, —NO₂, —NR^(2ba)C(═O)R^(2ba), —NR^(2ba)C(═O)OR^(2ba),—NR^(2ba)C(═O)N(R^(2ba))₂, —OC(═O)R^(2ba), —OC(═O)OR^(2ba), or—OC(═O)N(R^(2ba))₂, and each instance of R^(2ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(2ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R² is substituted or unsubstituted heterocyclyl.In certain embodiments, R² is substituted or unsubstituted 3-6 memberedheterocyclyl, e.g., oxetanyl, tetrahydrofuranyl, pyranyl, azetidinyl,pyrrolidinyl, or piperidinyl. In certain embodiments, R² is 3-6 memberedheterocyclyl substituted with 1, 2, 3, 4, or 5 instances of R^(2b),wherein each instance of R^(2b) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(2ba), —N(R^(2ba))₂,—SR^(2ba), —CN, —SCN, —C(═NR^(2ba))R^(2ba), —C(═NR^(2ba))OR^(2ba),—C(═NR^(2ba))N(R^(2ba))₂, —C(═O)R^(2ba), —C(═O)OR^(2ba),—C(═O)N(R^(2ba))₂, —NO₂, —NR^(2ba)C(═O)R^(2ba), —NR^(2ba)C(═O)OR^(2ba),—NR^(2ba)C(═O)N(R^(2ba))₂, —OC(═O)R^(2ba), —OC(═O)OR^(2ba), or—OC(═O)N(R^(2ba))₂ and each instance of R^(2ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(2ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R² is substituted or unsubstituted aryl. Incertain embodiments, R² is substituted or unsubstituted phenyl. Incertain embodiments, R² is phenyl substituted with 1, 2, 3, 4, or 5instances of R^(2b), wherein each instance of R^(2b) is independentlyhalogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(2ba), —N(R^(2ba))₂, —SR^(2ba), —CN, —SCN,—C(═NR^(2ba))R^(2ba), —C(═NR^(2ba))OR^(2ba), —C(═NR^(2ba))N(R^(2ba))₂,—C(═O)R^(2ba), —C(═O)OR^(2ba), —C(═O)N(R^(2ba))₂, —NO₂,—NR^(2ba)C(═O)R^(2ba), —NR^(2ba)C(═O)OR^(2ba),—NR^(2ba)C(═O)N(R^(2ba))₂, —OC(═O)R^(2ba), —OC(═O)OR^(2ba), or—OC(═O)N(R^(2ba))₂ and each instance of R^(2ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(2ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R² is substituted or unsubstituted heteroaryl.In certain embodiments, R² is substituted or unsubstituted 5-6 memberedheteroaryl, e.g., pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isothiazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl,or pyridizinyl. In certain embodiments, R² is 5-6 membered heteroarylsubstituted with 1, 2, 3, 4, or 5 instances of R^(2b), wherein eachinstance of R^(2b) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(2ba), —N(R^(2ba))₂,—SR^(2ba), —CN, —SCN, —C(═NR^(2ba))R^(2ba), —C(═NR^(2ba))OR^(2ba),—C(═NR^(2ba))N(R^(2ba))₂, —C(═O)R^(2ba), —C(═O)OR^(2ba),—C(═O)N(R^(2ba))₂, —NO₂, —NR^(2ba)C(═O)R^(2ba), —NR^(2ba)C(═O)OR^(2ba),—NR^(2ba)C(═O)N(R^(2ba))₂, —OC(═O)R^(2ba), —OC(═O)OR^(2ba), or—OC(═O)N(R^(2ba))₂ and each instance of R^(2ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(2ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R² is —C(═O)R^(D1), —C(═O)OR^(D1), or—C(═O)N(R^(D1))₂. In certain embodiments, R² is C(═O)R^(D1); and R^(D1)is substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl. In certainembodiments, R² is —C(═O)OR^(D1); and R^(D1) is substituted orunsubstituted alkyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl. In certain embodiments,R² is —C(═O)N(R^(D1))₂; and each instance of R^(D1) is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group, or two R^(D1) groups are joinedto form a substituted or unsubstituted heterocyclic or substituted orunsubstituted heteroaryl ring.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isnot hydrogen. In certain embodiments, R³ is substituted or unsubstitutedC₁₋₆ alkyl, e.g., methyl, ethyl, propyl, or butyl. In certainembodiments, R³ is unsubstituted methyl. In certain embodiments, R³ isunsubstituted ethyl. In certain embodiments, R³ is unsubstitutedn-propyl. In certain embodiments, R³ is branched C₁₋₆ alkyl, e.g.,isopropyl, isobutyl, or t-butyl. In certain embodiments, R³ isunsubstituted isopropyl. In certain embodiments, R³ is unsubstitutedt-butyl. In certain embodiments, R³ is substituted or unsubstituted C₁₋₆haloalkyl, e.g., —CF₃, —CH₂CF₃, —CHF₂, —CH₂F, —CF₂CH₃, or —CF₂CF₃. Incertain embodiments, R³ is substituted or unsubstituted aralkyl, e.g.,benzyl. In certain embodiments, R³ is substituted or unsubstitutedalkoxyalkyl, e.g., —CH₂OR^(3a), —CH₂CH₂OR^(3a), or —CH₂CH(CH₃)OR^(3a),wherein R^(3a) is substituted or unsubstituted C₁₋₆ alkyl, substitutedor unsubstituted C₁₋₆ haloalkyl, or substituted or unsubstituted phenyl.

In certain embodiments, R³ is substituted or unsubstituted alkenyl,e.g., vinyl, allyl, propenyl, or butenyl. In certain embodiments, R³ issubstituted or unsubstituted alkynyl, e.g., propargyl, propynyl, orbutynyl.

In certain embodiments, R³ is substituted or unsubstituted carbocyclyl.In certain embodiments, R³ is substituted or unsubstituted 3-6 memberedcarbocyclyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In certain embodiments, R³ is unsubstituted cyclopropyl. In certainembodiments, R³ is unsubstituted cyclobutyl. In certain embodiments, R³is unsubstituted cyclopentyl. In certain embodiments, R³ isunsubstituted cyclohexyl. In certain embodiments, R³ is 3-6 memberedcarbocyclyl substituted with 1, 2, 3, 4, or 5 instances of R^(3b),wherein each instance of R^(3b) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(3b), —N(R^(3ba))₂,—SR^(3ba), —CN, —SCN, —C(═NR^(3ba))R^(3ba), —C(═NR^(3ba))OR^(3ba),—C(═NR^(3ba))N(R^(3ba))₂, —C(═O)R^(3ba), —C(═O)OR^(3ba),—C(═O)N(R^(3ba))₂, —NO₂, —NR^(3ba)C(═O)R^(3ba), —NR^(3ba)C(═O)OR^(3ba),—NR^(3ba)C(═O)N(R^(3ba))₂, —OC(═O)R^(3ba), —OC(═O)OR^(3ba), or—OC(═O)N(R^(3ba))₂ and each instance of R^(3ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(3ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R³ is substituted or unsubstituted heterocyclyl.In certain embodiments, R³ is substituted or unsubstituted 3-6 memberedheterocyclyl, e.g., oxetanyl, tetrahydrofuranyl, pyranyl, azetidinyl,pyrrolidinyl, or piperidinyl. In certain embodiments, R³ is 3-6 memberedheterocyclyl substituted with 1, 2, 3, 4, or 5 instances of R^(3b),wherein each instance of R^(3b) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(3ba), —N(R^(3ba))₂,—SR^(3ba), —CN, —SCN, —C(═NR^(3ba))R^(3ba), —C(═NR^(3ba))OR^(3ba),—C(═NR^(3ba))N(R^(3ba))₂, —C(═O)R^(3ba), —C(═O)OR^(3ba),—C(═O)N(R^(3ba))₂, —NO₂, —NR^(3ba)C(═O)R^(3ba), —NR^(3ba)C(═O)OR^(3ba),—NR^(3ba)C(═O)N(R^(3ba))₂, —OC(═O)R^(3ba), —OC(═O)OR^(3ba), or—OC(═O)N(R^(3ba))₂ and each instance of R^(3ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(3ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R³ is substituted or unsubstituted aryl. Incertain embodiments, R³ is substituted or unsubstituted phenyl. Incertain embodiments, R³ is phenyl substituted with 1, 2, 3, 4, or 5instances of R^(3b), wherein each instance of R^(3b) is independentlyhalogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(3ba), —N(R^(3ba))₂, —SR^(3ba), —CN, —SCN,—C(═NR^(3ba))R^(3ba), —C(═NR^(3ba))OR^(3ba), —C(═NR^(3ba))N(R^(3ba))₂,—C(═O)R^(3ba), —C(═O)OR^(3ba), —C(═O)N(R^(3ba))₂, —NO₂,—NR^(3ba)C(═O)R^(3ba), —NR^(3ba)C(═O)OR^(3ba),—NR^(3ba)C(═O)N(R^(3ba))₂, —OC(═O)R^(3ba), —OC(═O)OR^(3ba), or—OC(═O)N(R^(3ba))₂ and each instance of R^(3ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(3ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R³ is substituted or unsubstituted heteroaryl.In certain embodiments, R³ is substituted or unsubstituted 5-6 memberedheteroaryl, e.g., pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isothiazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl,or pyridizinyl. In certain embodiments, R³ is 5-6 membered heteroarylsubstituted with 1, 2, 3, 4, or 5 instances of R^(3b), wherein eachinstance of R^(3b) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(3ba), —N(R^(3ba))₂,—SR^(3ba), —CN, —SCN, —C(═NR^(3ba))R^(3ba), —C(═NR^(3ba))OR^(3ba),—C(═NR^(3ba))N(R^(3ba))₂, —C(═O)R^(3ba), —C(═O)OR^(3ba),—C(═O)N(R^(3ba))₂, —NO₂, —NR^(3ba)C(═O)R^(3ba), —NR^(3ba)C(═O)OR^(3ba),—NR^(3ba)C(═O)N(R^(3ba))₂, —OC(═O)R^(3ba), —OC(═O)OR^(3ba), or—OC(═O)N(R^(3ba))₂ and each instance of R^(3ba) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(3ba) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R³ is —C(═O)R^(D1), —C(═O)OR^(D1), or—C(═O)N(R^(D1))₂. In certain embodiments, R² is —C(═O)R^(D1); and R^(D1)is substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl. In certainembodiments, R³ is —C(═O)OR^(D1); and R^(D1) is substituted orunsubstituted alkyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl. In certain embodiments,R³ is —C(═O)N(R^(D1))₂; and each instance of R^(D1) is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group, or two R^(D1) groups are joinedto form a substituted or unsubstituted heterocyclic or substituted orunsubstituted heteroaryl ring.

Ring B, Group R^(B1) and p

As generally defined herein, each instance of R^(B1) is independentlyhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(B1a), —N(R^(B1a))₂, —SR^(B1a), —CN, —SCN,—C(═NR^(B1a))R^(B1a), —C(═NR^(B1a))OR^(B1a), —C(═NR^(B1a))N(R^(B1a))₂,—C(═O)R^(B1a), —C(═O)OR^(B1a), —C(═O)N(R^(B1a))₂, —NO₂,—NR^(B1a)C(═O)R^(B1a), —NR^(B1a)C(═O)OR^(B1a),—NR^(B1a)C(═O)N(R^(B1a))₂, —OC(═O)R^(B1a), —OC(═O)OR^(B1a), or—OC(═O)N(R^(B1a))₂. As generally defined herein, each instance ofR^(B1a) is independently hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(B1a)groups are joined to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring. As generally definedherein, p is 0 or an integer between 1 and 4, inclusive. In certainembodiments, p is 1.

In certain embodiments, p is 0. In certain embodiments, p is 1. Incertain embodiments, p is 2. In certain embodiments, p is 3. In certainembodiments, p is 4.

When Formula (I) includes two or more instances of R^(B1), any twoinstances of R^(B1) may be the same or not the same. In certainembodiments, all instances of R^(B1) are the same. In certainembodiments, at least one instance of R^(B1) is hydrogen. In certainembodiments, each instance of R^(B1) is hydrogen. In certainembodiments, at least one instance of R^(B1) is halogen (e.g., F, Cl,Br, or I). In certain embodiments, at least one instance of R^(B1) issubstituted or unsubstituted alkyl (e.g., substituted or unsubstitutedC₁₋₆ alkyl (e.g., Me)). In certain embodiments, at least one instance ofR^(B1) is —OR^(B1a). In certain embodiments, at least one instance ofR^(B1) is not —OR^(B1a). In certain embodiments, at least one instanceof R^(B1) is —OR^(B1a); and R^(B1a) is substituted or unsubstitutedalkyl. In certain embodiments, at least one instance of R^(B1) is—OR^(B1a); and R^(B1a) is substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, at least one instance of R^(B1) is OR^(B1a); andR^(B1a) is substituted or unsubstituted C₂₋₆ alkyl. In certainembodiments, at least one instance of R^(B1) is —OR^(B1a); and R^(B1a)is methyl. In certain embodiments, at least one instance of R^(B1) is—OR^(B1a); and R^(B1a) is not methyl. In certain embodiments, at leastone instance of R^(B1) is —OR^(B1a); and R^(B1a) is ethyl. In certainembodiments, at least one instance of R^(B1) is —OR^(B1a); and R^(B1a)is substituted or unsubstituted C₁₋₆ haloalkyl. In certain embodiments,at least one instance of R^(B1) is —OR^(B1a); and R^(B1a) is substitutedor unsubstituted C₂₋₆ haloalkyl. In certain embodiments, at least oneinstance of R^(B1) is —OR^(B1a); and R^(B1a) is —CF₃.

In certain embodiments, the

group is ortho to the point of attachment of L¹ to ring B. In certainembodiments, the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments, the

group is para to the point of attachment of L¹ to ring B.

In certain embodiments,

is of the formula:

wherein each instance of R^(B1) is not hydrogen. In certain embodiments,

is of the formula:

wherein R^(B1) is not hydrogen.

In certain embodiments,

is of the formula:

wherein each instance of R^(B1) is not hydrogen. In certain embodiments,

is of the formula:

In certain embodiments,

is not

optionally R^(B1) is not hydrogen. In certain embodiments,

is not

In certain embodiments,

is not

In certain embodiments,

In certain embodiments,

In certain embodiments,

Linker L¹, R^(a1) and R^(c1)

As generally defined herein, L¹ is a bond,

As generally defined herein, R^(a1) is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or a nitrogen protectinggroup. As generally defined herein, each instance of R^(c1) isindependently hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(c1a), —N(R^(c1a))₂,—SR^(c1a), —CN, —C(═O)R^(c1a), —C(═O)OR^(c1a), —C(═O)N(R^(c1a))₂,—NR^(c1a)C(═O)R^(c1a), —NR^(c1a)C(═O)OR^(c1a),—NR^(c1a)C(═O)N(R^(c1a))₂, —OC(═O)R^(c1a), or —OC(═O)N(R^(c1a))₂. Asgenerally defined herein, each instance of R^(c1a) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(c1a) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R^(a1) is hydrogen. In certain embodiments,R^(a1) is not hydrogen. In certain embodiments, the two instances ofR^(c1) are the same. In certain embodiments, the two instances of R^(c1)are not the same. In certain embodiments, at least one instance ofR^(c1) is hydrogen. In certain embodiments, each instance of R^(c1) ishydrogen. In certain embodiments, at least one instance of R^(c1) is nothydrogen. In certain embodiments, L¹ is a bond,

In certain embodiments, L¹ is a bond,

In certain embodiments, L¹ is a bond. In certain embodiments, L¹ is

In certain embodiments, L¹ is

In certain embodiments, R^(a1) or at least one instance of R^(c1) issubstituted or unsubstituted C₁₋₆ alkyl, e.g., methyl, ethyl, propyl, orbutyl. In certain embodiments, R^(a1) or at least one instance of R^(c1)is unsubstituted methyl. In certain embodiments, R^(a1) or at least oneinstance of R^(c1) is unsubstituted ethyl. In certain embodiments,R^(a1) or at least one instance of R^(c1) is unsubstituted n-propyl. Incertain embodiments, R^(a1) or at least one instance of R^(c1) isbranched C₁₋₆ alkyl, e.g., isopropyl, isobutyl, or t-butyl. In certainembodiments, R^(a1) or at least one instance of R^(c1) is unsubstitutedisopropyl. In certain embodiments, R^(a1) or at least one instance ofR^(c1) is unsubstituted t-butyl. In certain embodiments, R^(a1) or atleast one instance of R^(c1) is substituted or unsubstituted C₁₋₆haloalkyl, e.g., —CF₃, —CH₂CF₃, —CHF₂, —CH₂F, —CF₂CH₃, or —CF₂CF₃. Incertain embodiments, R^(a1) or at least one instance of R^(c1) issubstituted or unsubstituted aralkyl, e.g., benzyl. In certainembodiments, R^(a1) or at least one instance of Rd is substituted orunsubstituted alkoxyalkyl, e.g., —CH₂OR^(a1a), —CH₂CH₂OR^(a1a),—CH₂CH(CH₃)OR^(a1a), wherein R^(a1a) is substituted or unsubstitutedC₁₋₆ alkyl, substituted or unsubstituted C₁₋₆ haloalkyl, or substitutedor unsubstituted phenyl.

In certain embodiments, R^(a1) or at least one instance of R^(c1) issubstituted or unsubstituted alkenyl, e.g., vinyl, allyl, propenyl, orbutenyl. In certain embodiments, R^(a1) or at least one instance ofR^(c1) is substituted or unsubstituted alkynyl, e.g., propargyl,propynyl, or butynyl.

In certain embodiments, R^(a1) or at least one instance of R^(c1) issubstituted or unsubstituted carbocyclyl. In certain embodiments, R^(a1)or at least one instance of R^(c1) is substituted or unsubstituted 3-6membered carbocyclyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In certain embodiments, R^(a1) or at least one instance ofR^(c1) is unsubstituted cyclopropyl. In certain embodiments, R^(a1) orat least one instance of R^(c1) is unsubstituted cyclobutyl. In certainembodiments, R^(a1) or at least one instance of R^(c1) is unsubstitutedcyclopentyl. In certain embodiments, R^(a1) or at least one instance ofR^(c1) is unsubstituted cyclohexyl. In certain embodiments, R^(a1) or atleast one instance of R^(c1) is 3-6 membered carbocyclyl substitutedwith 1, 2, 3, 4, or 5 instances of R^(1x), wherein each instance ofR^(1x) is independently halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(1y), —N(R^(1y))₂,—SR^(1y), —CN, —SCN, —C(═NR^(1y))R^(1y), —C(═NR^(1y))OR^(1y),—C(═NR^(1y))N(R^(1y))₂, —C(═O)R^(1y), —C(═O)OR^(1y), —C(═O)N(R^(1y))₂,—NO₂, —NR^(1y)C(═O)R^(1y), —NR^(1y)C(═O)OR^(1y),—NR^(1y)C(═O)N(R^(1y))₂, —OC(═O)R^(1y), —OC(═O)OR^(1y), or—OC(═O)N(R^(1y))₂ and each instance of R^(1y) is independently hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(1y) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R^(a1) or at least one instance of R^(c1) issubstituted or unsubstituted heterocyclyl. In certain embodiments,R^(a1) or at least one instance of R^(c1) is substituted orunsubstituted 3-6 membered heterocyclyl, e.g., oxetanyl,tetrahydrofuranyl, pyranyl, azetidinyl, pyrrolidinyl, or piperidinyl. Incertain embodiments, R^(a1) or at least one instance of R^(c1) is 3-6membered heterocyclyl substituted with 1, 2, 3, 4, or 5 instances ofR^(1x), wherein each instance of R^(1x) is independently halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(1y), —N(R^(1y))₂, —SR^(1y), —CN, —SCN,—C(═NR^(1y))R^(1y), —C(═NR^(1y))OR^(1y), —C(═NR^(1y))N(R^(1y))₂,—C(═O)R^(1y), —C(═O)OR^(1y), —C(═O)N(R^(1y))₂, —NO₂,—NR^(1y)C(═O)R^(1y), —NR^(1y)C(═O)OR^(1y), —NR^(1y)C(═O)N(R^(1y))₂,—OC(═O)R^(1y), —OC(═O)OR^(1y), or —OC(═O)N(R^(1y))₂ and each instance ofR^(1y) is independently hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(1y)groups are joined to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring.

In certain embodiments, R^(a1) or at least one instance of R^(c1) issubstituted or unsubstituted aryl. In certain embodiments, R^(a1) or atleast one instance of R^(c1) is substituted or unsubstituted phenyl. Incertain embodiments, R^(a1) or at least one instance of R^(c1) is phenylsubstituted with 1, 2, 3, 4, or 5 instances of R^(1x), wherein eachinstance of R^(1x) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(1y), —N(R^(1y))₂,—SR^(1y), —CN, —SCN, —C(═NR^(1y))R^(1y), —C(═NR^(1y))OR^(1y),—C(═NR^(1y))N(R^(1y))₂, —C(═O)R^(1y), —C(═O)OR^(1y), —C(═O)N(R^(1y))₂,—NO₂, —NR^(1y)C(═O)R^(1y), —NR^(1y)C(═O)OR^(1y),—NR^(1y)C(═O)N(R^(1y))₂, —OC(═O)R^(1y), —OC(═O)OR^(1y), or—OC(═O)N(R^(1y))₂ and each instance of R^(1y) is independently hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(1y) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring.

In certain embodiments, R^(a1) or at least one instance of R^(c1) issubstituted or unsubstituted heteroaryl. In certain embodiments, R^(a1)or at least one instance of R^(c1) is substituted or unsubstituted 5-6membered heteroaryl, e.g., pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isothiazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl,or pyridizinyl. In certain embodiments, R^(a1) or at least one instanceof R^(c1) is 5-6 membered heteroaryl substituted with 1, 2, 3, 4, or 5instances of R^(1x), wherein each instance of R^(1x) is independentlyhalogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(1y), —N(R^(1y))₂, —SR^(1y), —CN, —SCN,—C(═NR^(1y))R^(1y), —C(═NR^(1y))OR^(1y), —C(═NR^(1y))N(R^(1y))₂,—C(═O)R^(1y), —C(═O)OR^(1y), —C(═O)N(R^(1y))₂, —NO₂,—NR^(1y)C(═O)R^(1y), —NR^(1y)C(═O)OR^(1y), —NR^(1y)C(═O)N(R^(1y))₂,—OC(═O)R^(1y), —OC(═O)OR^(1y), or —OC(═O)N(R^(1y))₂ and each instance ofR^(1y) is independently hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two R^(1y)groups are joined to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring.

Additional Formulae

In certain embodiments, the compound of Formula (I) is of Formula (I-1):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-1), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-1), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-1), R^(B) is hydrogen. In certain embodimentsof Formula (I-1), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-1), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula (I-2):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-2), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-2), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-2), R^(B) is hydrogen. In certain embodimentsof Formula (I-2), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-2), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula (I-3):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-3), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-3), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-3), R^(B) is hydrogen. In certain embodimentsof Formula (I-3), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-3), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula (I-4):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-4), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-4), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-4), R^(B) is hydrogen. In certain embodimentsof Formula (I-4), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-4), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula (I-5):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-5), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-5), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-5), R^(B) is hydrogen. In certain embodimentsof Formula (I-5), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-5), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula (I-6):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-6), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-6), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-6), R^(B) is hydrogen. In certain embodimentsof Formula (I-6), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-6), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula (I-7):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-7), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-7), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-7), R^(B) is hydrogen. In certain embodimentsof Formula (I-7), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-7), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula (I-8):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-8), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-8), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-8), R^(B) is hydrogen. In certain embodimentsof Formula (I-8), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-8), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula (I-9):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-9), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-9), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-9), R^(B) is hydrogen. In certain embodimentsof Formula (I-9), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-9), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-10):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-10), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-10), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-10), R^(B) is hydrogen. In certain embodimentsof Formula (I-10), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-10), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-11):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-11), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-11), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-11), R^(B) is hydrogen. In certain embodimentsof Formula (I-11), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-11), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-12):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-12), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-12), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-12), R^(B) is hydrogen. In certain embodimentsof Formula (I-12), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-12), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-13):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-13), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-13), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-13), R^(B) is hydrogen. In certain embodimentsof Formula (I-13), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-13), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-14):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-14), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-14), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-14), R^(B) is hydrogen. In certain embodimentsof Formula (I-14), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-14), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-15):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-15), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-15), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-15), R^(B) is hydrogen. In certain embodimentsof Formula (I-15), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-15), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-16):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-16), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-16), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-16), R^(B) is hydrogen. In certain embodimentsof Formula (I-16), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-16), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-17):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-17), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-17), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-17), R^(B) is hydrogen. In certain embodimentsof Formula (I-17), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-17), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-18):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-18), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-18), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-18), R^(B) is hydrogen. In certain embodimentsof Formula (I-18), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-18), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-19):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-19), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-19), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-19), R^(B) is hydrogen. In certain embodimentsof Formula (I-19), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-19), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-20):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-20), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-20), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-20), R^(B) is hydrogen. In certain embodimentsof Formula (I-20), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-20), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-21):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-21), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-21), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-21), R^(B) is hydrogen. In certain embodimentsof Formula (I-21), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-21), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-22):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-22), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-22), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-22), R^(B) is hydrogen. In certain embodimentsof Formula (I-22), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-22), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-23):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-23), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-23), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-23), R^(B) is hydrogen. In certain embodimentsof Formula (I-23), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-23), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-24):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-24), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-24), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-24), R^(B) is hydrogen. In certain embodimentsof Formula (I-24), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-24), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-25):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-25), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-25), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-25), R^(B) is hydrogen. In certain embodimentsof Formula (I-25), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-25), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-26):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-26), the

group is para to the point of attachment of L to ring B. In certainembodiments of Formula (I-26), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-26), R^(B) is hydrogen. In certain embodimentsof Formula (I-26), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-26), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-27):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-27), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-27), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-27), R^(B) is hydrogen. In certain embodimentsof Formula (I-27), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-27), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-28):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-28), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-28), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-28), R^(B) is hydrogen. In certain embodimentsof Formula (I-28), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-28), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-29):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-29), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-29), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-29), R^(B) is hydrogen. In certain embodimentsof Formula (I-29), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-29), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-30):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-30), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-30), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-30), R^(B) is hydrogen. In certain embodimentsof Formula (I-30), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-30), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-31):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-31), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-31), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-31), R^(B) is hydrogen. In certain embodimentsof Formula (I-31), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-31), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-32):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-32), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-32), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-32), R^(B) is hydrogen. In certain embodimentsof Formula (I-32), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-32), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-33):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-33), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-33), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-33), R^(B) is hydrogen. In certain embodimentsof Formula (I-33), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-33), R^(C) is hydrogen.

In certain embodiments, the compound of Formula (I) is of Formula(I-34):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments of Formula (I-34), the

group is para to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-34), the

group is meta to the point of attachment of L¹ to ring B. In certainembodiments of Formula (I-34), R^(B) is hydrogen. In certain embodimentsof Formula (I-34), neither R^(A) nor R^(B) is hydrogen. In certainembodiments of Formula (I-34), R^(C) is hydrogen.Specific Compounds

In certain embodiments, a compound of Formula (I) is a compound in TableA, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. In certain embodiments, a compound of Formula (I) is acompound in Table B, or a pharmaceutically acceptable salt, solvate,hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallylabeled derivative, or prodrug thereof. In certain embodiments, acompound of Formula (I) is a compound in Table C, or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof.

TABLE A Exemplary compounds of Formula (I)

R^(A)

TABLE B Exemplary compounds of Formula (I)

R^(A) or R^(B) R^(B) or R^(A)

TABLE C Exemplary compounds of Formula (I)

In certain embodiments, R^(C) of a compound shown in Table A, B, or C ishydrogen. In certain embodiments, a compound described herein is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallylabeled derivative, or prodrug thereof. In certain embodiments, acompound described herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof.

Compounds described herein have been found to bindbromodomain-containing proteins. In certain embodiments, the compoundsdescribed herein bind to a bromodomain-containing protein. Withoutwishing to be bound by any particular theory, the compounds describedherein are thought to bind in a pocket of a bromodomain of abromodomain-containing protein. In certain embodiments, the compoundsdescribed herein bind in the binding pocket of the bromodomain bymimicking the contact between an acetyl-lysine residue of a secondprotein (e.g., a histone) and the binding pocket. In certainembodiments, the compounds described herein bind in the binding pocketof the bromodomain. In certain embodiments, the compounds describedherein covalently bind to the bromodomain-containing protein. In certainembodiments, the compounds described herein non-covalently bind to thebromodomain-containing protein. In certain embodiments, the compoundsdescribed herein reversibly bind to the bromodomain-containing protein.In certain embodiments, the compounds described herein non-reversiblybind to the bromodomain-containing protein. In certain embodiments, thecompounds described herein inhibit the activity (e.g., aberrantactivity, increased activity) of a bromodomain-containing protein. Incertain embodiments, the compounds described herein inhibit the activity(e.g., aberrant activity, increased activity) of a bromodomain. Incertain embodiments, the activity of a bromodomain is the ability of thebromodomain to bind an acetylated lysine residue (e.g., an acetylatedlysine residue on the N-terminal tails of histones), which may be partof another protein or peptide. In certain embodiments, the compoundsdescribed herein specifically bind to a bromodomain-containing protein(e.g., bind to a bromodomain-containing protein with a higher bindingaffinity than to a different bromodomain-containing protein and/or to aprotein that is not a bromodomain-containing protein). In certainembodiments, the compounds described herein specifically bind to abromodomain of a bromodomain-containing protein (e.g., bind to abromodomain of a bromodomain-containing protein with a higher bindingaffinity than to a non-bromodomain of the bromodomain-containingprotein). In certain embodiments, the compounds described hereinnon-specifically bind to a bromodomain-containing protein (e.g., bind toa bromodomain of the bromodomain-containing protein). In certainembodiments, the compounds described herein reduce transcriptionalelongation. In certain embodiments, the compounds described hereindisrupt the subcellular localization of a bromodomain-containingprotein. In certain embodiments, the compounds described herein reducechromatin binding. In certain embodiments, the compounds describedherein inhibit the formation of a chromatin by reducing the binding of aprotein (e.g., histone) to a DNA. In certain embodiments, the compoundsdescribed herein inhibit the binding of Histone H4 Kac peptide to abromodomain of a bromodomain-containing protein. In certain embodiments,the compounds described herein form one or more hydrogen bonds with anevolutionarily conserved asparagine in a bromodomain of abromodomain-containing protein. In certain embodiments, the asparagineis Asn140 in BRD4(1) and Asn429 in BRD2(2). In certain embodiments, thebromodomain-containing protein is BRD4 or BRD2; and the asparagine isAsn140 in BRD4(1) and Asn429 in BRD2(2). In certain embodiments, thecompounds described herein bind competitively with chromatin in acellular environment. It is thus expected that the compounds describedherein may be useful in the treatment of a disease associated with theactivity a bromodomain-containing protein (e.g., a proliferativedisease).

The compounds described herein may bind bromodomain-containing proteinsand may inhibit the activity of the bromodomain-containing proteins. Incertain embodiments, the bromodomain-containing protein is a bromo andextra terminal (BET) protein. In certain embodiments, thebromodomain-containing protein is BRD2. In certain embodiments, thebromodomain-containing protein is BRD2(1). In certain embodiments, thebromodomain-containing protein is BRD2(2). In certain embodiments, thebromodomain-containing protein is BRD3. In certain embodiments, thebromodomain-containing protein is BRD3(1). In certain embodiments, thebromodomain-containing protein is BRD3(2). In certain embodiments, thebromodomain-containing protein is BRD4. In certain embodiments, thebromodomain-containing protein is BRD4(1). In certain embodiments, thebromodomain-containing protein is BRD4(2). In certain embodiments, thebromodomain-containing protein is BRDT. In certain embodiments, thebromodomain-containing protein is BRDT(1). In certain embodiments, thebromodomain-containing protein is BRDT(2). In certain embodiments, thebromodomain-containing protein is a TBP (TATA box bindingprotein)-associated factor protein (TAF). In certain embodiments, thebromodomain-containing protein is TAF1. In certain embodiments, thebromodomain-containing protein is TAF1L. In certain embodiments, thebromodomain-containing protein is CREB-binding protein (CBP). In certainembodiments, the bromodomain-containing protein is E1A binding proteinp300 (EP300).

The binding affinity of a compound described herein to abromodomain-containing protein may be measured by the dissociationconstant (K_(d)) value of an adduct of the compound described herein andthe bromodomain-containing protein using methods known in the art (e.g.,isothermal titration calorimetry (ITC)). In certain embodiments, theadduct comprises the compound described herein and thebromodomain-containing protein, which are bound (e.g., covalently ornon-covalently) to each other. In certain embodiments, the K_(d) valueof the adduct is at most about 100 μM, at most about 30 μM, at mostabout 10 μM, at most about 3 μM, at most about 1 μM, at most about 300nM, at most about 100 nM, at most about 30 nM, at most about 10 nM, atmost about 3 nM, or at most about 1 nM. In certain embodiments, theK_(d) value of the adduct is at least about 1 nM, at least about 10 nM,at least about 100 nM, at least about 1 μM, at least about 10 μM, or atleast about 100 μM. Combinations of the above-referenced ranges (e.g.,at most about 10 μM and at least about 1 nM) are also within the scopeof the disclosure. Other ranges are also possible. In certainembodiments, the K_(d) value of the adduct is at most about 10 μM. Incertain embodiments, the K_(d) value of the adduct is at most about 300nM. In certain embodiments, the K_(d) value of the adduct is at mostabout 100 nM.

In certain embodiments, the activity of the bromodomain-containingproteins described herein is inhibited by the compounds describedherein. The inhibition of the activity of a bromodomain-containingprotein by a compound described herein may be measured by the halfmaximal inhibitory concentration (IC₅₀) value of a compound describedherein when the compound described herein, or a pharmaceuticalcomposition thereof, is contacted with the bromodomain-containingprotein. In certain embodiments, IC₅₀ values are obtained by acompetition binding assay. In certain embodiments, IC₅₀ values areobtained by a method described herein. In certain embodiments, the IC₅svalue of a compound described herein is at most about 1 mM, at mostabout 300 μM, at most about 100 μM, at most about 30 μM, at most about10 μM, at most about 3 μM, at most about 1 μM, at most about 300 nM, atmost about 100 nM, at most about 30 nM, at most about 10 nM, at mostabout 3 nM, or at most about 1 nM. In certain embodiments, the IC₅₀value of a compound described herein is at least about 1 nM, at leastabout 3 nM, at least about 10 nM, at least about 30 nM, at least about100 nM, at least about 300 nM, at least about 1 μM, at least about 3 μM,at least about 10 μM, at least about 30 μM, at least about 100 μM, atleast about 300 μM, or at least 1 mM. Combinations of theabove-referenced ranges (e.g., at most about 300 μM and at least about 1μM) are also within the scope of the disclosure. Other ranges are alsopossible. In certain embodiments, the IC₅₀ value of a compound describedherein is at most about 300 μM. In certain embodiments, the IC₅₀ valueof a compound described herein is at most about 30 μM. In certainembodiments, the IC₅₀ value of a compound described herein is at mostabout 10 μM.

The compounds described herein may selectively inhibit the activity of abromodomain-containing protein. In certain embodiments, the compoundsdescribed herein selectively inhibit the activity of abromodomain-containing protein compared to a differentbromodomain-containing protein. In certain embodiments, the compoundsdescribed herein selectively inhibit the activity of abromodomain-containing protein compared to a protein that is not abromodomain-containing protein. In certain embodiments, the compoundsdescribed herein selectively inhibit the activity of abromodomain-containing protein compared to a kinase (e.g., a kinasedescribed herein). In certain embodiments, the compounds describedherein selectively inhibit the activity of a bromodomain-containingprotein compared to MPS1 (TTK), ERK5 (BMK1, MAPK7), a polo kinase (e.g.,polo kinase 1, polo kinase 2, polo kinase 3, polo kinase 4), Ack1, Ack2,AbI, DCAMKL1, ABL1, an AbI mutant, DCAMKL2, ARK5, BRK, MKNK2, FGFR4,TNK1, PLK1, ULK2, PLK4, PRKD1, PRKD2, PRKD3, ROS 1, RPS6KA6, TAOK1,TAOK3, TNK2, Bcr-Abl, GAK, cSrc, TPR-Met, Tie2, MET, FGFR3, Aurora, AxI,Bmx, BTK, c-kit, CHK2, Flt3, MST2, p70S6K, PDGFR, PKB, PKC, Raf, ROCK-H,Rsk1, SGK, TrkA, TrkB, and/or TrkC. In certain embodiments, thecompounds described herein selectively inhibit the activity of abromodomain-containing protein compared to a MAP kinase. In certainembodiments, the compounds described herein selectively inhibit theactivity of a bromodomain-containing protein compared to a mitoticspindle kinase. In certain embodiments, the compounds described hereinselectively inhibit the activity of a bromodomain-containing proteincompared to a polo kinase. In certain embodiments, the compoundsdescribed herein selectively inhibit a BET protein. In certainembodiments, the compounds described herein selectively inhibit BRD2. Incertain embodiments, the compounds described herein selectively inhibitBRD3. In certain embodiments, the compounds described herein selectivelyinhibit BRD4. In certain embodiments, the compounds described hereinselectively inhibit BRDT. In certain embodiments, the compoundsdescribed herein selectively inhibit a TAF protein (e.g., TAF1 orTAF1L), CBP, and/or EP300. In certain embodiments, a compound describedherein is a non-selective inhibitor of two or morebromodomain-containing proteins. In certain embodiments, a compounddescribed herein is a non-selective inhibitor of abromodomain-containing protein and a protein that is not abromodomain-containing protein.

The selectivity of a compound described herein in inhibiting theactivity of a bromodomain-containing protein over a second protein(e.g., a kinase) that is different from the bromodomain-containingprotein may be measured by the quotient of the IC₅₀ value of thecompound described herein in inhibiting the activity of the secondprotein over the IC₅₀ value of the compound described herein ininhibiting the activity of the bromodomain-containing protein. Theselectivity of a compound described herein for a bromodomain-containingprotein over a second protein may also be measured by the quotient ofthe K_(d) value of an adduct of the compound described herein and thesecond protein over the K_(d) value of an adduct of the compounddescribed herein and the bromodomain-containing protein. In certainembodiments, the selectivity is at least about 1-fold, at least about3-fold, at least about 5-fold, at least about 10-fold, at least about30-fold, at least about 100-fold, at least about 300-fold, at leastabout 1,000-fold, at least about 3,000-fold, at least about 10,000-fold,at least about 30,000-fold, or at least about 100,000-fold. In certainembodiments, the selectivity is at most about 100,000-fold, at mostabout 10,000-fold, at most about 1,000-fold, at most about 100-fold, atmost about 10-fold, or at most about 1-fold. Combinations of theabove-referenced ranges (e.g., at least about 2-fold and at most about10,000-fold) are also within the scope of the disclosure. Other rangesare also possible. In certain embodiments, the selectivity is at leastabout 3-fold. In certain embodiments, the selectivity is at least about10-fold. In certain embodiments, the selectivity is at least about50-fold. In certain embodiments, the selectivity is at least about100-fold. In certain embodiments, the selectivity is at least about1,000-fold.

It is known in the art that a bromodomain-containing protein isimplicated in a wide range of diseases. For example, BRD3 and BRD4 arerelated to BRD3 NUT midline carcinoma and BRD4 NUT midline carcinoma,respectively. BRDT is related to sperm formation, and CBP is related tomixed-lineage leukemia (MLL). Therefore, the compounds described hereinare expected to be useful in treating and/or preventing diseasesassociated with bromodomain-containing proteins or as a malecontraceptive.

Pharmaceutical Compositions

The present disclosure provides pharmaceutical compositions comprising acompound described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof), and optionally a pharmaceutically acceptableexcipient. In certain embodiments, the pharmaceutical compositiondescribed herein comprises a compound of Formula (I), or apharmaceutically acceptable salt thereof, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical composition described herein comprises a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In certain embodiments, the compound described herein is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylacticallyeffective amount. In certain embodiments, the effective amount is anamount effective for treating and/or preventing a disease (e.g., adisease described herein) in a subject in need thereof. In certainembodiments, the effective amount is an amount effective for treating adisease in a subject in need thereof. In certain embodiments, theeffective amount is an amount effective for preventing a disease in asubject in need thereof. In certain embodiments, the effective amount isan amount effective for reducing the risk of developing a disease in asubject in need thereof. In certain embodiments, the effective amount isan amount effective for male contraception (e.g., effective forinhibiting sperm formation) in a subject in need thereof. In certainembodiments, the effective amount is an amount effective for inhibitingthe replication of a virus. In certain embodiments, the effective amountis an amount effective for killing a virus. In certain embodiments, theeffective amount is an amount effective for inhibiting the activity(e.g., aberrant activity, such as increased activity) of abromodomain-containing protein in a subject or cell. In certainembodiments, the effective amount is an amount effective for inhibitingthe activity (e.g., aberrant activity, such as increased activity) of abromodomain in a subject or cell. In certain embodiments, the effectiveamount is an amount effective for inhibiting the binding of abromodomain of a bromodomain-containing protein to an acetyl-lysineresidue of a second protein (e.g., a histone) in a subject or cell. Incertain embodiments, the effective amount is an amount effective formodulating (e.g., inhibiting) transcriptional elongation in a subject orcell. In certain embodiments, the effective amount is an amounteffective for modulating (e.g., down-regulating or inhibiting) theexpression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein in a subject or cell. In certainembodiments, the effective amount is an amount effective for inducingapoptosis of a cell. In certain embodiments, the effective amount is anamount effective for inducing apoptosis in a subject. In certainembodiments, the effective amount is an amount effective for inducing G1arrest in a subject or cell. An effective amount of a compound may varyfrom about 0.001 mg/kg to about 1000 mg/kg in one or more doseadministrations for one or several days (depending on the mode ofadministration). In certain embodiments, the effective amount per dosevaries from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kgto about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150mg/kg.

In certain embodiments, the effective amount is an amount effective forinhibiting the activity of a bromodomain-containing protein, theactivity of a bromodomain, the binding of a bromodomain of abromodomain-containing protein to an acetyl-lysine residue of a secondprotein (e.g., a histone), the transcriptional elongation, and/or theexpression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein, for inducing or increasing apoptosis, orfor inducing or increasing G1 arrest by at least about 10%, at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90%, at least about 95%, or at least about 98%. In certainembodiments, the effective amount is an amount effective for inhibitingthe activity of a bromodomain-containing protein, the binding of abromodomain of a bromodomain-containing protein to an acetyl-lysineresidue of a second protein (e.g., a histone), and/or the expression(e.g., transcription) of a gene that is regulated by abromodomain-containing protein by at most about 90%, at most about 80%,at most about 70%, at most about 60%, at most about 50%, at most about40%, at most about 30%, at most about 20%, or at most about 10%.Combinations of the ranges described herein (e.g., at least about 20%and at most about 50%) are also within the scope of the disclosure. Incertain embodiments, the activity of a bromodomain-containing protein,the binding of a bromodomain of a bromodomain-containing protein to anacetyl-lysine residue of a second protein (e.g., a histone), and/or theexpression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein are inhibited by a percentage or a rangeof percentage described herein by an effective amount of a compounddescribed herein.

In certain embodiments, the gene regulated by a bromodomain-containingprotein is a gene regulated by a bromo and extra terminal protein (BET).In certain embodiments, the gene regulated by a bromodomain-containingprotein is BRD2. In certain embodiments, the gene regulated by abromodomain-containing protein is BRD2(1). In certain embodiments, thegene regulated by a bromodomain-containing protein is BRD2(2). Incertain embodiments, the gene regulated by a bromodomain-containingprotein is BRD3. In certain embodiments, the gene regulated by abromodomain-containing protein is BRD3(1). In certain embodiments, thegene regulated by a bromodomain-containing protein is BRD3(2). Incertain embodiments, the gene regulated by a bromodomain-containingprotein is BRD4. In certain embodiments, the gene regulated by abromodomain-containing protein is BRD4(1). In certain embodiments, thegene regulated by a bromodomain-containing protein is BRD4(2). Incertain embodiments, the gene regulated by a bromodomain-containingprotein is BRDT. In certain embodiments, the gene regulated by abromodomain-containing protein is BRDT(1). In certain embodiments, thegene regulated by a bromodomain-containing protein is BRDT(2). Incertain embodiments, the gene regulated by a bromodomain-containingprotein is a gene regulated by a TBP (TATA box bindingprotein)-associated factor protein (TAF). In certain embodiments, thegene regulated by a bromodomain-containing protein is TAF1. In certainembodiments, the gene regulated by a bromodomain-containing protein isTAF1L. In certain embodiments, the gene regulated by abromodomain-containing protein is a gene regulated by a CREB-bindingprotein (CBP). In certain embodiments, the gene regulated by abromodomain-containing protein is a gene regulated by an E1A bindingprotein p300 (EP300).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound described herein(i.e., the “active ingredient”) into association with a carrier orexcipient, and/or one or more other accessory ingredients, and then, ifnecessary and/or desirable, shaping, and/or packaging the product into adesired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage such as, for example, one-half or one-third ofsuch a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g., acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays(e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminumsilicate)), long chain amino acid derivatives, high molecular weightalcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.,carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60),polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate(Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate(Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80),polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45),polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g., Cremophor®),polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic® F-68, Poloxamer P-188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g., cornstarch and starchpaste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g., acacia, sodium alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate(Veegum®), and larch arabogalactan), alginates, polyethylene oxide,polyethylene glycol, inorganic calcium salts, silicic acid,polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, antiprotozoanpreservatives, alcohol preservatives, acidic preservatives, and otherpreservatives. In certain embodiments, the preservative is anantioxidant. In other embodiments, the preservative is a chelatingagent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®,Kathon®, and Euxyl®.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, chamomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol, or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of encapsulating agents which can be usedinclude polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compounddescribed herein may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier or excipient and/or any neededpreservatives and/or buffers as can be required. Additionally, thepresent disclosure contemplates the use of transdermal patches, whichoften have the added advantage of providing controlled delivery of anactive ingredient to the body. Such dosage forms can be prepared, forexample, by dissolving and/or dispensing the active ingredient in theproper medium. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing theactive ingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices. Intradermalcompositions can be administered by devices which limit the effectivepenetration length of a needle into the skin. Alternatively oradditionally, conventional syringes can be used in the classical mantouxmethod of intradermal administration. Jet injection devices whichdeliver liquid formulations to the dermis via a liquid jet injectorand/or via a needle which pierces the stratum corneum and produces a jetwhich reaches the dermis are suitable. Ballistic powder/particledelivery devices which use compressed gas to accelerate the compound inpowder form through the outer layers of the skin to the dermis aresuitable.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi-liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions. Topicallyadministrable formulations may, for example, comprise from about 1% toabout 10% (w/w) active ingredient, although the concentration of theactive ingredient can be as high as the solubility limit of the activeingredient in the solvent. Formulations for topical administration mayfurther comprise one or more of the additional ingredients describedherein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers, or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self-propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions described herein formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition describedherein. Another formulation suitable for intranasal administration is acoarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) to as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition described herein can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1/1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier or excipient. Such dropsmay further comprise buffering agents, salts, and/or one or more otherof the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are alsocontemplated as being within the scope of this disclosure.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration). In certain embodiments, the compoundor pharmaceutical composition described herein is suitable for topicaladministration to the eye of a subject.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. The desired dosage can be delivered three times a day, twotimes a day, once a day, every other day, every third day, every week,every two weeks, every three weeks, or every four weeks. In certainembodiments, the desired dosage can be delivered using multipleadministrations (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or more administrations).

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds described herein may be at dosagelevels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg,from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kgto about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg,from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic and/or prophylactic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionalpharmaceutical agents (e.g., therapeutically and/or prophylacticallyactive agents). The compounds or compositions can be administered incombination with additional pharmaceutical agents that improve theiractivity (e.g., activity (e.g., potency and/or efficacy) in treating adisease in a subject in need thereof, in preventing a disease in asubject in need thereof, in reducing the risk of developing a disease ina subject in need thereof, in inhibiting the replication of a virus, inkilling a virus, in inhibiting the activity of a bromodomain-containingprotein in a subject or cell, in inhibiting the activity of abromodomain in a subject or cell, in inhibiting the binding of abromodomain of a bromodomain-containing protein to an acetyl-lysineresidue of a second protein (e.g., a histone) in a subject or cell, inmodulating (e.g., inhibiting) the transcription elongation, inmodulating (e.g., inhibiting) the expression (e.g., transcription) of agene that is regulated by a bromodomain-containing protein in a subjector cell, in inducing apoptosis of a cell, in inducing apoptosis in asubject, or in inducing G1 arrest in a subject or cell),bioavailability, and/or safety, reduce drug resistance, reduce and/ormodify their metabolism, inhibit their excretion, and/or modify theirdistribution within the body of a subject. It will also be appreciatedthat the therapy employed may achieve a desired effect for the samedisorder, and/or it may achieve different effects. In certainembodiments, a pharmaceutical composition described herein including acompound described herein and an additional pharmaceutical agent shows asynergistic effect that is absent in a pharmaceutical compositionincluding one of the compound and the additional pharmaceutical agent,but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichmay be useful as, e.g., combination therapies. Pharmaceutical agentsinclude therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Pharmaceutical agents includesmall organic molecules such as drug compounds (e.g., compounds approvedfor human or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful for treating and/or preventing a diseasedescribed herein. Each additional pharmaceutical agent may beadministered at a dose and/or on a time schedule determined for thatpharmaceutical agent. The additional pharmaceutical agents may also beadministered together with each other and/or with the compound orcomposition described herein in a single dose or administered separatelyin different doses. The particular combination to employ in a regimenwill take into account compatibility of the compound described hereinwith the additional pharmaceutical agent(s) and/or the desiredtherapeutic and/or prophylactic effect to be achieved. In general, it isexpected that the additional pharmaceutical agent(s) utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually.

The additional pharmaceutical agents include, but are not limited to,anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents,anti-inflammatory agents, immunosuppressants, anti-bacterial agents,anti-viral agents, cardiovascular agents, cholesterol-lowering agents,anti-diabetic agents, anti-allergic agents, contraceptive agents, andpain-relieving agents. In certain embodiments, the additionalpharmaceutical agent is an anti-proliferative agent. In certainembodiments, the additional pharmaceutical agent is an anti-canceragent. In certain embodiments, the additional pharmaceutical agent is ananti-viral agent. In certain embodiments, the additional pharmaceuticalagent is a binder of a bromodomain-containing protein. In certainembodiments, the additional pharmaceutical agent is a binder of abromodomain. In certain embodiments, the additional pharmaceutical agentis a binder or inhibitor of a bromodomain-containing protein. In certainembodiments, the additional pharmaceutical agent is an binder orinhibitor of a bromodomain. In certain embodiments, the additionalpharmaceutical agent is selected from the group consisting of epigeneticor transcriptional modulators (e.g., DNA methyltransferase inhibitors,histone deacetylase inhibitors (HDAC inhibitors), lysinemethyltransferase inhibitors), antimitotic drugs (e.g., taxanes andvinca alkaloids), hormone receptor modulators (e.g., estrogen receptormodulators and androgen receptor modulators), cell signaling pathwayinhibitors (e.g., tyrosine kinase inhibitors), modulators of proteinstability (e.g., proteasome inhibitors), Hsp90 inhibitors,glucocorticoids, all-trans retinoic acids, and other agents that promotedifferentiation. In certain embodiments, the compounds described hereinor pharmaceutical compositions can be administered in combination withan anti-cancer therapy including, but not limited to, surgery, radiationtherapy, and chemotherapy.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orcompound described herein and a container (e.g., a vial, ampule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or compound described herein.In some embodiments, the pharmaceutical composition or compounddescribed herein provided in the first container and the secondcontainer are combined to form one unit dosage form.

Thus, in one aspect, provided are kits including a first containercomprising a compound described herein, or a pharmaceutically acceptablesalt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, or prodrug thereof, or a pharmaceuticalcomposition thereof. In certain embodiments, the kits are useful fortreating and/or preventing a disease described herein in a subject inneed thereof. In certain embodiments, the kits are useful for treating adisease described herein in a subject in need thereof. In certainembodiments, the kits are useful for preventing a disease describedherein in a subject in need thereof. In certain embodiments, the kitsare useful for reducing the risk of developing a disease describedherein in a subject in need thereof. In certain embodiments, the kitsare useful for male contraception. In certain embodiments, the kits areuseful for inhibiting sperm formation. In certain embodiments, the kitsare useful for in inhibiting the replication of a virus. In certainembodiments, the kits are useful for killing a virus. In certainembodiments, the kits are useful for inhibiting the activity (e.g.,aberrant activity, such as increased activity) of abromodomain-containing protein in a subject or cell. In certainembodiments, the kits are useful for inhibiting the activity (e.g.,aberrant activity, such as increased activity) of a bromodomain in asubject or cell. In certain embodiments, the kits are useful forinhibiting the binding of a bromodomain of a bromodomain-containingprotein to an acetyl-lysine residue of a second protein (e.g., ahistone) in a subject or cell. In certain embodiments, the kits areuseful for modulating (e.g., inhibiting) the transcriptional elongationin a subject or cell. In certain embodiments, the kits are useful formodulating (e.g., down-regulating or inhibiting) the expression (e.g.,transcription) of a gene that is regulated by a bromodomain-containingprotein in a subject or cell. In certain embodiments, the kits areuseful for inducing apoptosis of a cell. In certain embodiments, thekits are useful for inducing apoptosis in a subject. In certainembodiments, the kits are useful for inducing G1 arrest in a subject orcell.

In certain embodiments, the kits are useful for screening a library ofcompounds to identify a compound that is useful in a method of thedisclosure.

In certain embodiments, a kit described herein further includesinstructions for using the kit, such as instructions for using the kitin a method of the disclosure (e.g., instructions for administering acompound or pharmaceutical composition described herein to a subject). Akit described herein may also include information as required by aregulatory agency such as the U.S. Food and Drug Administration (FDA).In certain embodiments, the information included in the kits isprescribing information. In certain embodiments, the kits andinstructions provide for treating and/or preventing a disease describedherein in a subject in need thereof. In certain embodiments, the kitsand instructions provide for treating a disease described herein in asubject in need thereof. In certain embodiments, the kits andinstructions provide for preventing a disease described herein in asubject in need thereof. In certain embodiments, the kits andinstructions provide for reducing the risk of developing a diseasedescribed herein in a subject in need thereof. In certain embodiments,the kits and instructions provide for male contraception. In certainembodiments, the kits and instructions provide for inhibiting thereplication of a virus. In certain embodiments, the kits andinstructions provide for killing a virus. In certain embodiments, thekits and instructions provide for inhibiting the activity (e.g.,aberrant activity, such as increased activity) of abromodomain-containing protein in a subject or cell. In certainembodiments, the kits and instructions provide for inhibiting theactivity (e.g., aberrant activity, such as increased activity) of abromodomain in a subject or cell. In certain embodiments, the kits andinstructions provide for inhibiting the binding of a bromodomain of abromodomain-containing protein to an acetyl-lysine residue of a secondprotein (e.g., a histone) in a subject or cell. In certain embodiments,the kits and instructions provide for modulating (e.g., inhibiting) thetranscriptional elongation. In certain embodiments, the kits andinstructions provide for modulating (e.g., down-regulating orinhibiting) the expression (e.g., transcription) of a gene that isregulated by a bromodomain-containing protein in a subject or cell. Incertain embodiments, the kits and instructions provide for inducingapoptosis of an in vitro cell. In certain embodiments, the kits andinstructions provide for inducing apoptosis of a cell in a subject. Incertain embodiments, the kits and instructions provide for inducing G1arrest in a subject or cell. In certain embodiments, the kits andinstructions provide for screening a library of compounds to identify acompound that is useful in a method of the disclosure. A kit describedherein may include one or more additional pharmaceutical agentsdescribed herein as a separate composition.

Methods of Treatment

The present disclosure provides methods for the treatment of a widerange of diseases, such as diseases associated with bromodomains,diseases associated with the activity (e.g., aberrant activity) ofbromodomains, diseases associated with bromodomain-containing proteins,and disease associated with the activity (e.g., aberrant activity) ofbromodomain-containing proteins. Exemplary diseases include, but are notlimited to, proliferative diseases, cardiovascular diseases, viralinfections, fibrotic diseases, neurological diseases, metabolicdiseases, endocrine diseases, and radiation poisoning. Also provided bythe present disclosure are methods for male contraception. The presentdisclosure also provides methods of inhibiting sperm formation. Thepresent disclosure further provides methods of inhibiting the activity(e.g., aberrant activity, such as increased activity) of a bromodomainor bromodomain-containing protein, methods of inhibiting the binding ofa bromodomain of a bromodomain-containing protein to an acetyl-lysineresidue of a second protein (e.g., a histone), methods of modulating(e.g., inhibiting) the transcriptional elongation, methods of modulating(e.g., down-regulating or inhibiting) the expression (e.g.,transcription) of a gene that is regulated by a bromodomain-containingprotein, methods of inducing apoptosis, and methods of inducing G1arrest.

Gene regulation is fundamentally governed by reversible, non-covalentassembly of macromolecules. Signal transduction to RNA polymeraserequires higher-ordered protein complexes, spatially regulated byassembly factors capable of interpreting the post-translationalmodification states of chromatin. Epigenetic readers are structurallydiverse proteins, and each of the epigenetic readers possesses one ormore evolutionarily conserved effector modules, which recognize covalentmodifications of proteins (e.g., histones) or DNA. The ε-N-acetylationof lysine residues (Kac) on histone tails is associated with an openchromatin architecture and transcriptional activation. Context-specificmolecular recognition of acetyl-lysine is principally mediated bybromodomains.

Bromodomain-containing proteins are of substantial biological interest,as components of transcription factor complexes (e.g., TBP (TATA boxbinding protein)-associated factor 1 (TAF1), CREB-binding protein (CBPor CREBBP), P300/CBP-associated factor (PCAF), and Gcn5) anddeterminants of epigenetic memory. There are 41 human proteinscontaining a total of 57 diverse bromodomains. Despite large sequencevariations, all bromodomains share a conserved fold comprising aleft-handed bundle of four alpha helices (α_(Z), α_(A), α_(B), andα_(C)), linked by diverse loop regions (ZA and BC loops) that determinesubstrate specificity. Co-crystal structures with peptidic substratesshowed that the acetyl-lysine is recognized by a central hydrophobiccavity and is anchored by a hydrogen bond with an asparagine residuepresent in most bromodomains. The bromo and extra-terminal (BET) family(e.g., BRD2, BRD3, BRD4 and BRDT) shares a common domain architecturecomprising two N-terminal bromodomains that exhibit a high degree ofsequence conservation, and a more divergent C-terminal recruitmentdomain.

Recent research has established a compelling rationale for targetingBRD4 in cancer. BRD4 functions to facilitate cell cycle progression, andknock-down in cultured cancer cell lines prompts G1 arrest. BRD4 is animportant mediator of transcriptional elongation, functioning to recruitthe positive transcription elongation factor complex (P-TEFb). Cyclindependent kinase-9, a core component of P-TEFb, is a validated target inchronic lymphocytic leukemia, and has recently been linked to c-Mycdependent transcription. Bromodomains present in BRD4 recruit P-TEFb tomitotic chromosomes resulting in increased expression of growthpromoting genes. BRD4 remains bound to transcriptional start sites ofgenes expressed during M/G1 but has not been found present at startsites that are expressed later in the cell cycle. Knockdown of BRD4 inproliferating cells has been shown to lead to G1 arrest and apoptosis bydecreasing expression levels of genes important for mitotic progressionand survival.

Importantly, BRD4 has recently been identified as a component of arecurrent t(15;19) chromosomal translocation in an aggressive form ofhuman squamous cell carcinoma. Such translocations express the tandemN-terminal bromodomains of BRD4 as an in-frame chimera with the nuclearprotein in testis (NUT) protein, genetically defining the NUT midlinecarcinoma (NMC). Functional studies in patient-derived NMC cell lineshave validated the essential role of the BRD4-NUT oncoprotein inmaintaining the characteristic proliferation advantage anddifferentiation block of this malignancy. Notably, RNA silencing ofBRD4-NUT gene expression arrests proliferation and prompts squamousdifferentiation with a marked increase in cytokeratin expression. Abromodomain may also down-regulates Myc and other transcripitionalfactors, such as interleukin 7 receptor (IL7R). These observationsunderscore the utility and therapeutic potential of a binder orinhibitor of bromodomain-containing proteins.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain-containing protein in a subject.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain-containing protein in a cell.

In certain embodiments, the bromodomain-containing protein is abromodomain-containing protein described herein (e.g., a BET protein,such as BRD2, BRD3, BRD4, or BRDT). In certain embodiments, the activityof a bromodomain-containing protein in a subject or cell is inhibited bythe described methods. In certain embodiments, the activity of abromodomain-containing protein in a subject or cell is inhibited by thedescribed methods by at least about 1%, at least about 3%, at leastabout 10%, at least about 20%, at least about 30%, at least about 40%,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, at least about 95%, or at least about98%. In certain embodiments, the activity of a bromodomain-containingprotein in a subject or cell is inhibited by the described methods by atmost about 90%, at most about 80%, at most about 70%, at most about 60%,at most about 50%, at most about 40%, at most about 30%, at most about20%, at most about 10%, at most about 3%, or at most about 1%.Combinations of the above-referenced ranges (e.g., at least about 10%and at most about 50%) are also within the scope of the disclosure.Other ranges are also possible. In some embodiments, the activity of abromodomain-containing protein in a subject or cell is selectivelyinhibited by the described methods. In some embodiments, the activity ofa bromodomain-containing protein in a subject or cell is selectivelyinhibited by the described methods, compared to the activity of a kinase(e.g., a MAP kinase, a mitotic spindle kinase, a polo kinase). In otherembodiments, the activity of a bromodomain-containing protein in asubject or cell is non-selectively inhibited by the described methods.In certain embodiments, the cytokine level and/or histamine release arereduced by the described methods.

In certain embodiments, the activity of a bromodomain-containing proteinis an aberrant activity of the bromodomain-containing protein. Incertain embodiments, the activity of a bromodomain-containing protein isan increased activity of the bromodomain-containing protein. In certainembodiments, the activity of a bromodomain-containing protein is reducedby a method of the disclosure.

In certain embodiments, the subject is an animal. The animal may be ofeither sex and may be at any stage of development. In certainembodiments, the subject is a male. In certain embodiments, the subjectis a female. In certain embodiments, the subject described herein is ahuman. In certain embodiments, the subject described herein is a humanmale. In certain embodiments, the subject described herein is a humanfemale. In certain embodiments, the subject is a human diagnosed ashaving a disease described herein. In certain embodiments, the subjectis a human diagnosed as being at a higher-than-normal risk of developinga disease described herein. In certain embodiments, the subject is ahuman suspected of having a disease described herein. In certainembodiments, the subject is a non-human animal. In certain embodiments,the subject is a fish. In certain embodiments, the subject is a mammal.In certain embodiments, the subject is a non-human mammal. In certainembodiments, the subject is a human or non-human mammal. In certainembodiments, the subject is a domesticated animal, such as a dog, cat,cow, pig, horse, sheep, or goat. In certain embodiments, the subject isa companion animal such as a dog or cat. In certain embodiments, thesubject is a livestock animal such as a cow, pig, horse, sheep, or goat.In certain embodiments, the subject is a zoo animal. In anotherembodiment, the subject is a research animal such as a rodent (e.g.,mouse, rat), dog, pig, or non-human primate. In certain embodiments, theanimal is a genetically engineered animal. In certain embodiments, theanimal is a transgenic animal (e.g., transgenic mice and transgenicpigs).

In certain embodiments, the cell described herein is in vitro. Incertain embodiments, the cell is ex vivo. In certain embodiments, thecell is in vivo.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain in a subject.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain in a cell.

In certain embodiments, the activity of a bromodomain is an aberrantactivity of the bromodomain. In certain embodiments, the activity of abromodomain is an increased activity of the bromodomain. In certainembodiments, the activity of a bromodomain is reduced by a method of thedisclosure.

Another aspect of the present disclosure relates to methods ofinhibiting the binding of a bromodomain of a bromodomain-containingprotein to an acetyl-lysine residue of a second protein (e.g., ahistone) in a subject.

Another aspect of the present disclosure relates to methods ofinhibiting the binding of a bromodomain of a bromodomain-containingprotein to an acetyl-lysine residue of a second protein (e.g., ahistone) in a cell.

In certain embodiments, the second protein is a protein with anacetyl-lysine residue. In certain embodiments, the second protein is nota bromodomain-containing protein. In certain embodiments, the secondprotein is a histone. In certain embodiments, the histone is selectedfrom the group consisting of H1, H2A, H2B, H3, H4, and H5. In certainembodiments, the binding of a bromodomain of the bromodomain-containingprotein to an acetyl-lysine residue of the second protein (e.g., ahistone) is inhibited by the described methods.

In another aspect, the present disclosure provides methods of modulating(e.g., inhibiting) the transcription elongation. In certain embodiments,the transcription elongation is modulated (e.g., inhibited) by thedescribed methods.

In another aspect, the present disclosure provides methods of modulatingthe expression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein in a subject.

In another aspect, the present disclosure provides methods of modulatingthe expression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein in a cell.

In certain embodiments, the present disclosure provides methods ofdown-regulating or inhibiting the expression (e.g., transcription) of agene that is regulated by a bromodomain-containing protein in a subjector cell. Without wishing to be bound by any particular theory, thecompounds and pharmaceutical compositions described herein may be ableto interfere with the binding of a bromodomain-containing protein to atranscriptional start site of the gene. In certain embodiments, thecompounds and pharmaceutical compositions described herein interferewith the recognition of acetyl-lysine by a bromodomain orbromodomain-containing protein during the expression (e.g.,transcription) of the gene. In certain embodiments, the compounds andpharmaceutical compositions described herein interfere with theanchoring of a bromodomain-containing protein to an acetylated chromatin(e.g., a bromodomain of the bromodomain-containing protein beinganchored to an acetyl-lysine of the acetylated chromatin) during theexpression (e.g., transcription) of the gene. In certain embodiments,the expression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein in a subject or cell is modulated by thedescribed methods. In certain embodiments, the expression (e.g.,transcription) of a gene that is regulated by a bromodomain-containingprotein in a subject or cell is down-regulated or inhibited by thedescribed methods. In certain embodiments, the gene that is regulated bya bromodomain-containing protein is an oncogene.

Another aspect of the present disclosure relates to methods of treatinga disease in a subject in need thereof.

In certain embodiments, the disease is associated with abromodomain-containing protein. In certain embodiments, the disease isassociated with the activity of a bromodomain-containing protein. Incertain embodiments, the disease is associated with the aberrantactivity or increased activity of a bromodomain-containing protein.

In certain embodiments, the disease is associated with a bromodomain(e.g., a bromodomain of a bromodomain-containing protein). In certainembodiments, the disease is associated with the activity of abromodomain. In certain embodiments, the disease is associated with theaberrant activity or increased activity of a bromodomain. In certainembodiments, the disease is associated with the function (e.g.,dysfunction) of a bromodomain.

In certain embodiments, the disease described herein is driven by atranscriptional activator. In certain embodiments, the transcriptionalactivator is Myc. In certain embodiments, the disease is associated witha NUT rearrangement. In certain embodiments, the disease is associatedwith aberrant Myc function. In certain embodiments, the disease isassociated with the interleukin 7 receptor (IL7R).

In certain embodiments, the disease is a proliferative disease (e.g., aproliferative disease described herein). In certain embodiments, thedisease is cancer (e.g., a cancer described herein). In certainembodiments, the disease is lung cancer. In certain embodiments, thedisease is multiple myeloma. In certain embodiments, the disease isneuroblastoma. In certain embodiments, the disease is colon cancer. Incertain embodiments, the disease is testicular cancer. In certainembodiments, the disease is ovarian cancer. In certain embodiments, thedisease is lung cancer (e.g., small-cell lung cancer or non-small-celllung cancer). In certain embodiments, the disease is NUT midlinecarcinoma (e.g., BRD3 NUT midline carcinoma or BRD4 NUT midlinecarcinoma). In certain embodiments, the disease is mixed-lineageleukemia (MLL). In certain embodiments, the disease is selected from thegroup consisting of Burkitt's lymphoma, breast cancer, colon cancer,neuroblastoma, glial blastoma multiforme, chronic lymphocytic leukemia,and squamous cell carcinoma.

In certain embodiments, the disease is a benign neoplasm (e.g., a benignneoplasm described herein).

In certain embodiments, the disease is an inflammatory disease (e.g., aninflammatory disease described herein). In certain embodiments, thedisease is a disease that involves an inflammatory response to aninfection with a bacterium, virus, fungus, parasite, and/or protozoon.In certain embodiments, the disease is selected from the groupconsisting of osteoarthritis, acute gout, multiple sclerosis, aninflammatory bowel disease (e.g., Crohn's disease and ulcerativecolitis), neuroinflammation, asthma, a chronic obstructive airwaysdisease, pneumonitis, myositis, eczema, dermatitis, acne, cellulitis, anocclusive disease, thrombosis, alopecia, nephritis, vasculitis,retinitis, uveitis, scleritis, sclerosing cholangitis, hypophysitis,thyroiditis, septic shock, systemic inflammatory response syndrome(SIRS), toxic shock syndrome, acute lung injury, ARDS (adult respiratorydistress syndrome), acute renal failure, burns, pancreatitis (e.g.,acute pancreatitis), post-surgical syndromes, sarcoidosis, Herxheimerreactions, encephalitis, myelitis, meningitis, and malaria. In certainembodiments, the disease is acute or chronic pancreatitis. In certainembodiments, the disease is burns. In certain embodiments, the diseaseis an inflammatory bowel disease. In certain embodiments, the disease isneuroinflammation. In certain embodiments, the disease is sepsis orsepsis syndrome. In certain embodiments, the disease isgraft-versus-host disease (GVHD).

In certain embodiments, the disease is an autoimmune disease (e.g., anautoimmune disease described herein). In certain embodiments, thedisease is rheumatoid arthritis. In certain embodiments, the disease ispsoriasis, systemic lupus erythematosus, vitiligo, a bullous skindisease.

In certain embodiments, the disease is a cardiovascular disease. Incertain embodiments, the disease is atherogenesis or atherosclerosis. Incertain embodiments, the disease is arterial stent occlusion, heartfailure (e.g., congestive heart failure), a coronary arterial disease,myocarditis, pericarditis, a cardiac valvular disease, stenosis,restenosis, in-stent-stenosis, angina pectoris, myocardial infarction,acute coronary syndromes, coronary artery bypass grafting, acardio-pulmonary bypass procedure, endotoxemia, ischemia-reperfusioninjury, cerebrovascular ischemia (stroke), renal reperfusion injury,embolism (e.g., pulmonary, renal, hepatic, gastro-intestinal, orperipheral limb embolism), or myocardial ischemia.

In certain embodiments, the disease is a viral infection. In certainembodiments, the disease is an infection caused by DNA virus. In certainembodiments, the disease is an infection caused by a dsDNA virus. Incertain embodiments, the disease is an infection caused by an ssDNAvirus. In certain embodiments, the disease is an infection caused by anRNA virus. In certain embodiments, the disease is an infection caused bya dsRNA virus. In certain embodiments, the disease is an infectioncaused by a (+)ssRNA virus. In certain embodiments, the disease is aninfection caused by a (−)ssRNA virus. In certain embodiments, thedisease is an infection caused by a reverse transcribing (RT) virus. Incertain embodiments, the disease is an infection caused by an ssRNA-RTvirus. In certain embodiments, the disease is an infection caused by adsDNA-RT virus. In certain embodiments, the disease is an infectioncaused by human immunodeficiency virus (HIV). In certain embodiments,the disease is an infection caused by acquired immunodeficiency syndrome(AIDS). In certain embodiments, the disease is an infection caused byhuman papillomavirus (HPV). In certain embodiments, the disease is aninfection caused by hepatitis C virus (HCV). In certain embodiments, thedisease is an infection caused by a herpes virus (e.g., herpes simplexvirus (HSV)). In certain embodiments, the disease is an infection causedby Ebola virus. In certain embodiments, the disease is an infectioncaused by severe acute respiratory syndrome (SARS). In certainembodiments, the disease is an infection caused by influenza virus. Incertain embodiments, the disease is an infection caused by an influenzavirus. In certain embodiments, the disease is an infection caused by aninfluenza A virus. In certain embodiments, the disease is human flu(e.g., human flu caused by H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2,H7N2, H7N3, or H10N7 virus). In certain embodiments, the disease is birdflu (e.g., bird flu caused by H5N1 or H7N9 virus). In certainembodiments, the disease is swine influenza (e.g., swine influenzacaused by H1N1, H1N2, H2N1, H3N1, H3N2, H2N3, or influenza C virus). Incertain embodiments, the disease is equine influenza (e.g., equineinfluenza caused by H7N7 or H3N8 virus). In certain embodiments, thedisease is canine influenza (e.g., canine influenza caused by H3N8virus). In certain embodiments, the disease is an infection caused by aninfluenza B virus. In certain embodiments, the disease is an infectioncaused by an influenza C virus. In certain embodiments, the disease isDengue fever, Dengue hemorrhagic fever (DHF), Dengue shock syndrome(DSS), hepatitis A, hepatitis B, hepatitis D, hepatitis E, hepatitis F,infection caused by Coxsackie A virus, infection caused by Coxsackie Bvirus, fulminant viral hepatitis, viral myocarditis, infection caused byparainfluenza virus, infection caused by an RS virus (RSV) (e.g., RSVbronchiolitis, RSV pneumonia, especially an infant and childhoodinfection caused by RSV and RSV pneumonia in the patients withcardiopulmonary disorders), infection caused by measles virus, infectioncaused by vesicular stomatitis virus, infection caused by rabies virus,Japanese encephalitis, infection caused by Junin virus, infection causedby human cytomegalovirus, infection caused by varicellovirus, infectioncaused by cytomegalovirus, infection caused by muromegalovirus,infection caused by proboscivirus, infection caused by roseolovirus,infection caused by lymphocryptovirus, infection caused by macavirus,infection caused by percavirus, infection caused by rhadinovirus,infection caused by poliovirus, infection caused by Marburg virus,infection caused by Lassa fever virus, Venezuelan equine encephalitis,infection caused by Rift Valley Fever virus, infection caused by Koreanhemorrhagic fever virus, infection caused by Crimean-Congo hemorrhagicfever virus, encephalitis, Saint Louise encephalitis, Kyasanur Forestdisease, Murray Valley encephalitis, tick-borne encephalitis, West Nileencephalitis, yellow fever, infection caused by adenovirus, infectioncaused by poxvirus, or a viral infection in subjects with immunedisorders.

In certain embodiments, the disease is a fibrotic condition. In certainembodiments, the disease is selected from the group consisting of renalfibrosis, post-operative stricture, keloid formation, hepatic cirrhosis,biliary cirrhosis, and cardiac fibrosis. In certain embodiments, thedisease is scleroderma. In certain embodiments, the disease isidiopathic pulmonary fibrosis.

In certain embodiments, the disease is an endocrine disease. In certainembodiments, the disease is Addison's disease.

In certain embodiments, the disease is a neurological disease (e.g.,Alzheimer's disease).

In certain embodiments, the disease is a metabolic disease. In certainembodiments, the disease is diabetes. In certain embodiments, thedisease is type 1 diabetes. In certain embodiments, the disease is TypeII diabetes or gestational diabetes. In certain embodiments, the diseaseis obesity. In certain embodiments, the disease is fatty liver (NASH orotherwise), cachexia, hypercholesterolemia, or a disorder of lipidmetabolism via the regulation of apolipoprotein A1 (APOA1).

In certain embodiments, the disease is radiation poisoning. In certainembodiments, the disease is radiation injury.

In certain embodiments, the disease is acute rejection of transplantedorgans or multi-organ dysfunction syndrome.

In still another aspect, the present disclosure provides methods ofpreventing a disease described herein in a subject in need thereof.

In yet another aspect, the present disclosure provides methods ofreducing the risk of developing a disease described herein in a subjectin need thereof.

In yet another aspect, the present disclosure provides methods for malecontraception in a male subject in need thereof.

In yet another aspect, the present disclosure provides methods ofinhibiting sperm formation in a subject in need thereof.

Another aspect of the present disclosure relates to methods ofinhibiting the replication of a virus. In certain embodiments, thereplication of the virus is inhibited by the described methods.

In certain embodiments, the virus described herein is in vitro. Incertain embodiments, the virus is ex vivo. In certain embodiments, thevirus is in vivo.

Another aspect of the present disclosure relates to methods of killing avirus. In certain embodiments, the virus is killed by the describedmethods.

Another aspect of the disclosure relates to methods of inhibiting theinteraction between a bromodomain-containing protein and animmunoglobulin (Ig) regulatory element in a subject.

Another aspect of the disclosure relates to methods of inhibiting theinteraction between a bromodomain-containing protein and animmunoglobulin (Ig) regulatory element in a cell.

Another aspect of the disclosure relates to methods of inducingapoptosis (e.g., apoptosis of a cancer cell) in a subject.

Another aspect of the disclosure relates to methods of inducingapoptosis of a cell (e.g., an in vitro cell, a cancer cell).

Another aspect of the disclosure relates to methods of method forinducing G1 arrest in a subject.

Another aspect of the disclosure relates to methods of method forinducing G1 arrest in a cell.

In certain embodiments, the methods of the disclosure includeadministering to a subject in need thereof an effective amount of acompound or pharmaceutical composition described herein. In certainembodiments, the methods of the disclosure include administering to asubject in need thereof a therapeutically effective amount of a compoundor pharmaceutical composition described herein. In certain embodiments,the methods of the disclosure include administering to a subject in needthereof a prophylactically effective amount of a compound orpharmaceutical composition described herein. In certain embodiments, themethods of the disclosure include contacting a cell with an effectiveamount of a compound or pharmaceutical composition described herein. Incertain embodiments, the methods of the disclosure include contacting avirus with an effective amount of a compound or pharmaceuticalcomposition described herein.

Another aspect of the disclosure relates to methods of modulating theexpression of a gene that is regulated by a bromodomain-containingprotein in a subject.

Another aspect of the disclosure relates to methods of modulating theexpression of a gene that is regulated by a bromodomain-containingprotein in a cell.

Methods of Screening a Library of Compounds

Another aspect of the disclosure relates to methods of screening alibrary of compounds, and pharmaceutical acceptable salts thereof, toidentify a compound, or a pharmaceutical acceptable salt thereof, thatis useful in the methods of the disclosure. In certain embodiments, themethods of screening a library include obtaining at least two differentcompounds described herein; and performing at least one assay using thedifferent compounds described herein. In certain embodiments, at leastone assay is useful in identifying a compound that is useful in thedescribed methods.

Typically, the methods of screening a library of compounds involve atleast one assay. In certain embodiments, the assay is performed todetect one or more characteristics associated with the treatment and/orprevention of a disease described herein, with the inhibition of theactivity of a bromodomain-containing protein, with the inhibition of theactivity of a bromodomain, with the inhibition of the binding of abromodomain to an acetyl-lysine residue of a second protein (e.g., ahistone), with the modulation (e.g., inhibition) of the transcriptionalelongation, with the modulation (e.g., inhibition) of the expression(e.g., transcription) of a gene that is regulated by abromodomain-containing protein, with the induction of apoptosis, and/orwith the induction of G1 arrest. The characteristics may be desiredcharacteristics (e.g., a disease having been treated, a disease havingbeen prevented, the risk of developing a disease having been reduced,the replication of a virus having been inhibited, a virus having beenkilled, the activity of a bromodomain-containing protein having beeninhibited, the activity of a bromodomain, the binding of a bromodomainto an acetyl-lysine residue of a second protein (e.g., a histone) havingbeen inhibited, the transcriptional elongation having been modulated(e.g., having been inhibited), the expression (e.g., transcription) of agene that is regulated by a bromodomain-containing protein having beenmodulated (e.g., having been inhibited), the apoptosis having beeninduced, or the G1 arrest having been induced). The characteristics maybe undesired characteristics (e.g., a disease having not been treated, adisease having not been prevented, the risk of developing a diseasehaving not been reduced, the replication of a virus having not beeninhibited, a virus not having been killed, the activity of abromodomain-containing protein having not been inhibited, the activityof a bromodomain having not been inhibited, the binding of a bromodomainto an acetyl-lysine residue of a second protein (e.g., a histone) havingnot been inhibited, the transcriptional elongation having not beenmodulated (e.g., having not been inhibited), the expression (e.g.,transcription) of a gene that is regulated by a bromodomain-containingprotein having not been modulated (e.g., having not been inhibited), theapoptosis having not been induced, or the G1 arrest having not beeninduced). The assay may be an immunoassay, such as a sandwich-typeassay, competitive binding assay, one-step direct test, two-step test,or blot assay. The step of performing at least one assay may beperformed robotically or manually. In certain embodiments, the assaycomprises (a) contacting a library of compounds with abromodomain-containing protein; and (b) detecting the binding of thelibrary of compounds to the bromodomain-containing protein. In certainembodiments, the assay comprises detecting the specific binding of thelibrary of compounds to the bromodomain-containing protein. In certainembodiments, the assay comprises detecting the specific binding of thelibrary of compounds to a bromodomain of the bromodomain-containingprotein. In certain embodiments, the detected binding of the library ofcompounds to the bromodomain-containing protein is useful in identifyingthe compound that is useful in the methods of the disclosure. In certainembodiments, the step of detecting the binding comprises usingdifferential scanning fluorimetry (DSF), isothermal titrationcalorimetry (ITC), and/or an amplified luminescence proximityhomogeneous assay (ALPHA). The step of performing at least one assay maybe performed in a cell (e.g., a cancer cell) in vitro, ex vivo, or invivo. In certain embodiments, the step of performing at least one assayis performed in a cell (e.g., a cancer cell) in vitro. In certainembodiments, the assay comprises (a) contacting a library of compoundswith a cell; and (b) detecting a decrease in cell proliferation, anincrease in cell death, and/or an increase in cell differentiation. Incertain embodiments, the cell death is apoptotic cell death. In certainembodiments, the cell differentiation is identified by detecting anincrease in cytokeratin expression. In certain embodiments, the step ofperforming at least one assay further comprises detecting a reduction intranscriptional elongation.

Uses

In another aspect, the present disclosure provides the compoundsdescribed herein for use in a method of the disclosure.

In still another aspect, the present disclosure provides thepharmaceutical compositions described herein for use in a method of thedisclosure.

In still another aspect, the present disclosure provides uses of thecompounds described herein in a method of the disclosure.

In further another aspect, the present disclosure provides uses of thepharmaceutical compositions described herein in a method of thedisclosure.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Example 1. Preparation of Compounds

Various synthetic methods may be used to prepare the inventive compoundsdescribed herein. In one embodiment, the inventive compounds areprepared using the sequence provided in Scheme 1. Reductive aminationusing amines S-1 and ketones or aldehydes S-2 provide intermediates S-3,wherein R^(s1) is hydrogen or substituted or unsubstituted alkyl. Incertain embodiments, R^(s1) is methyl. In certain embodiments, thecarbon to which R¹ is attached is a stereocenter of the(S)-configuration. In certain embodiments, the carbon to which R¹ isattached is a stereocenter of the (R)-configuration. In certainembodiments, the carbon to which R¹ is attached is a mixture ofstereocenters of the (R) and (S)-configurations.

In certain embodiments, R² may be incorporated through amine addition toa leaving group conjugate of R² (i.e., LG-R², wherein LG is leavinggroup as defined herein). Addition of the free amino group of S-3 intothe nitro heterocycle S-4, wherein X¹ and X² are halide, leads tointermediates S-5. In certain embodiments, R² may be incorporated usingthe methods described herein following the reduction step. Reduction ofthe nitro functionality in S-5 produces compounds S-6. In certainembodiments, the conditions for the reduction comprise a metal catalyst,e.g., palladium on carbon or Raney nickel. In certain embodiments, theconditions for the reduction comprise a metal at the (0) oxidationstate, e.g., iron(0), tin(0), or zinc(0). In certain embodiments, theconditions for the reduction comprise addition of an acid, e.g., aceticor hydrochloric acid. Cyclization of the free amino group leads tocompounds S-7. In certain embodiments, the reduction and cyclizationsteps occur in one pot. Various leaving group conjugates of R³ (i.e.,LG-R³, wherein LG is a leaving group as defined herein) can be contactedwith compounds S-7 under appropriate conditions to afford intermediatesS-8. In certain embodiments, the conditions comprise a base. In someembodiments, the conditions comprise an inorganic base, e.g., potassiumor sodium carbonate. In certain embodiments, the leaving group conjugateof R³ is an alkyl phosphate. Subsequent linkage of the B-ring throughintermediates S-9 can be accomplished under aromatic substitution orcoupling conditions to afford intermediates S-10, wherein Rx issubstituted or unsubstituted alkyl. In certain embodiments, theconditions comprise a base. In some embodiments, the conditions comprisean inorganic base, e.g., potassium or sodium carbonate. In certainembodiments, the conditions comprise an amide coupling reagent, e.g.,HATU or EDC. Hydrolysis of intermediates S-10 and subsequent couplingwith hydrazines affords intermediates S-11. In certain embodiments, theconditions comprise a base. In some embodiments, the conditions comprisean inorganic base, e.g., lithium hydroxide. In certain embodiments, theconditions comprise an acid. In certain embodiments, the conditionscomprise an inorganic acid, e.g., hydrofluoric acid. In certainembodiments, the conditions comprise an amide coupling reagent, e.g.,HATU or EDC. In certain embodiments, the conditions comprise achloroformate, e.g., methylchloroformate. Intermediates S-11 can then becondensed with aldehydes or ketones to yield compounds of Formula (I).In certain embodiments, the condensation reaction conditions compriseheating, e.g., to approximately between 100-200° C.

(R)-ethyl4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)benzoate

(R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one(100 mg) (see Budin et al., Angewandte Chemie, Int. Ed, 2011, 50, 9378),ethyl 4-aminobenzoate (67 mg) Pd₂dba₃ (15 mg), XPhos (23.3 mg), andpotassium carbonate (187 mg) were dissolved in tBuOH and heated to 100°C. for 20 hours. The mixture was filtered through celite, washed withDCM and evaporated. The material was purified by column chromatography(0 to 100% EtOAc/hexanes) to give the desired product (0.09 g of ayellow oil).

¹H NMR: (400 MHz, Chloroform-d) δ 8.04-7.94 (m, 2H), 7.66 (dd, J=6.7,2.1 Hz, 3H), 7.29 (s, 1H), 4.47 (p, J=8.3 Hz, 1H), 4.35 (q, J=7.1 Hz,2H), 4.23 (dd, J=7.9, 3.7 Hz, 1H), 3.32 (s, 3H), 2.17-2.09 (m, 1H),2.02-1.95 (m, 1H), 1.91-1.78 (m, 4H), 1.75-1.61 (m, 4H), 1.38 (t, J=7.1Hz, 3H), 0.87 (t, J=7.5 Hz, 3H). LCMS: 424.49 (M+H).

(R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)benzoicacid

(R)-ethyl4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)benzoate(0.09 g) was dissolved in THF (1.05 mL) and water (0.52 mL). LiOH (7.6mg) was added and the mixture was stirred for one day. Poor conversionwas observed and additional LiOH (7.6 mg) and methanol (0.52 mL) wereadded. The solution was stirred for an additional day and then purifieddirectly by HPLC (5 to 95% MeCN/H₂O with 0.1% TFA) to give the desiredproduct as a white solid (56 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.71 (m, 5H), 4.40 (s, 1H), 4.25 (s,1H), 3.25 (s, 3H), 2.05 (s, 1H), 1.91 (s, 1H), 1.86-1.70 (m, 5H),1.68-1.55 (m, 3H), 0.79 (t, J=7.5 Hz, 3H). LCMS: 396.44 (M+H).

(R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)benzohydrazide

(R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)benzoicacid (56 mg) was dissolved in DCM and THF and cooled in an ice bath.Triethylamine (0.1 mL) and ClCO₂Me (0.032 mL) were then added and themixture was stirred for 1 hour. Hydrazine (0.044 mL) was then added andthe mixture was stirred for an additional 2 hours. The mixture was thendiluted with 5 mL of saturated sodium bicarbonate (aq) and extractedthree times with EtOAc. The combined organic phase was dried over sodiumsulfate, filtered and condensed. The material was purified by HPLC (5 to95% MeCN/H₂O with 0.1% TFA) to give the desired product (16.3 mg). LCMS:410.47 (M+H).

Additional LC-MS Data (See Plate Map 1, FIG. 1A):

Well B8: found: 559.58, expected 559.28 (M+H). Well A7: found: 501.56,expected 501.27 (M+H). Well C1: found: 502.55, expected 502.27 (M+H).Well H1: found: 524.58, expected 568.17 (M+H). Well A9: found: 515.56,expected 515.25 (M+H). Well A3: found 488.52, expected 488.25 (M+H).Well F10: found 504.56, expected 504.31 (M+H). Well H11: found 592.60,expected 598.74 (M+H).

Example 2. Biochemical and Cellular Assays of the CompoundsAcetyl-Histone Binding Assay

Assays were performed with minor modifications from the manufacturer'sprotocol (PerkinElmer, USA). All reagents were diluted in 50 mM HEPES,150 mM NaCl, 0.1% w/v BSA, and 0.01% w/v Tween® 20 at pH 7.5 and allowedto equilibrate to room temperature prior to addition to plates. Afteraddition of Alpha beads to master solutions, all subsequent steps wereperformed in low light conditions. A 2× solution of components withfinal concentrations of BRD4.1 at 80 nM, Ni-coated Acceptor Bead at 25μg/ml, and 80 nM biotinylated H4-tetra acetyl was added in 10 μL to384-well plates (AlphaPlate—384, PerkinElmer, USA). Biotinylated peptidefor BRD4.1 was synthesized in-house on a CEM Liberty 9008005 microwavepeptide synthesizer: H4-tetra acetyl,biotin-PEG2-SGRGKacGGKacGLGKacGGAKacRHRK-COOH. Addition to wells wasperformed with either a multichannel pipet (for optimizationexperiments) or a Biotek EL406 liquid handler. After a 1000-rpmspin-down for 1 minute, 100 nL of the solutions of the compounds of theinvention from stock plates were added by pin transfer using a JanusWorkstation (PerkinElmer, USA). The streptavidin-coated donor beads (25μg/ml final) were added as with previous solution in a 2×, 10 μL volume.Following this addition, the plates were sealed with foil to block lightexposure and to prevent evaporation. The plates were spun down again at1000 rpm for 1 minute. Next, the plates were incubated in the room withthe plate reader (for temperature equilibration) for 1.5 hour prior toreading the assay. AlphaScreen® measurements were performed on anEnvision 2104 (PerkinElmer, USA) utilizing the manufacturer's protocol.

Cellular Assay

The compounds of the invention were also evaluated in a BRD4 dependantcell line for the cellular activity to generate cellular IC₅₀ inhibitionvalues.

Cells (e.g., BRD4-dependant cells) were counted and adjusted to 60,000cells/mL. Using a Biotek EL406, 50 μL of the cells in media weredistributed into 384-well white plates from Thermo. Immediately afterplating, compounds of the invention in DMSO were distributed to plates.For large plate sets, cells were returned to a 37° C. incubator whilenot in use. The compounds were added to plates using a 100 nL 384-wellpin transfer manifold on a Janus workstation. Stocks were arrayed in 10point quadruplicate dose response in DMSO stock in 384-well Greinercompound plates. After addition of the compounds, plates were incubatedfor three days in a 37° C. incubator. Cell viability was read out usingATPlite from Perkin Elmer. Plates were removed from the incubator andbrought to room temperature prior to use. Lyophilized powder wasresuspended in lysis buffer and diluted 1:2 with DI water. 25 μL of thissolution was added to each well using the Biotek liquid handler. Plateswere sealed with adherent aluminum seals prior to vortexing andcentrifugation at 1000 g for 1 minute. Plates were incubated for 15minutes at room temperature before signal was read on an Envision PlateReader.

Isothermal Titration Calorimetery

ITC was performed using a ITC200 microcalorimeter from GE™ (Northampton,Mass.). All experiments were carried out at 25° C. while stirring at1000 rpm, in ITC buffer (50 mM HEPES pH 7.4 at 25° C., 150 mM NaCl). Themicrosyringe was loaded with a solution of the protein sample (225 μM,in ITC buffer). The compound solution (22.5 μM, in ITC buffer) wastitrated into the protein solution via syringe. All titrations wereconducted using an initial injection of 0.2 μl, followed by 19 identicalinjections of 2 μl with a duration of 5 sec (per injection) and aspacing of 90 sec between injections. The heat of dilution wasdetermined by independent titrations (protein into buffer) and wassubtracted from the experimental data. The collected data wereimplicated in the MicroCal® Origin software supplied with the instrumentto yield enthalpies of binding (ΔH) and binding constants (K_(a)). Thecollected data were implicated in the MicroCal® Origin software suppliedwith the instrument to yield enthalpies of binding (ΔH) and bindingconstants (K_(B)). Thermodynamic parameters were calculated(ΔG=ΔH−TΔS=−RT ln K_(B), where ΔG, ΔH and ΔS are the changes in freeenergy, enthalpy and entropy of binding, respectively). A single bindingsite model was employed.

Cell Cycle Analysis by Flow Cytometry

797, MOLM-13, and HL60 cells were plated in T-75 flasks and grown inDMEM (797) or RPMI (MOLM-13 and HL60) containing 10% fetal bovine serumand 1% penicillin/streptomycin. Cells were treated with compound at 1 μM(797) or 500 nM (MOLM-13 and HL60), or the equivalent volume of DMSO for24 hours. 2×106 cells were spun at 500×g for minutes at 4° C. and washedwith PBS. Pellets were resuspended in 1 mL of cold PBS and addeddropwise while gently vortexing to 9 mL 70% ethanol in a 15 mLpolypropylene centrifuge tube. Fixed cells were then frozen at −20° C.overnight. The next day, cells were centrifuged at 500×g for 10 minutesat 4° C. and washed with 3 mL of cold PBS. Cells were resuspended in 500μL of propidium iodide staining solution (0.2 mg/mL RNAse A, 0.2 mg/mLpropidium iodide, 01.% Triton-X in PBS) and incubated for 20 min at 37°C. Samples were then transferred to ice and analyzed on a BD FACS CantoII. Histograms were generated, and cell cycle analysis was performedusing ModFit flow cytometry analysis software.

Results

Shown in FIGS. 3A, 3B, 4A, and 4B are the in vitro inhibition values ofseveral representative compounds of Formula (I) for BRD4 and BRDT in anALPHA assay. In FIG. 3A, top panel, the compounds, from left to right ofthe X-axis, are the compounds of the positions C1, H1, D9, A3, G8, A1,H11, D7, H3, F3, C11, C2, B1, F10, A7, C3, G12, B8, G10, H4, H7, F1, G9,F6, D3, D2, D5, G3, E11, G5, E1, E3, F9, A5, H10, A10, E6, G2, H8, G6,D10, E10, A2, D1, B10, D8, B2, D6, C10, D11, A4, F5, B4, E7, E9, F4, F7,A9, H12, H2, H9, G1, F2, G4, B7, H5, B5, B9, A6, E2, F8, C7, A8, A11,C6, H6, B11, E8, C8, D4, B6, C9, E4, C4, E5, G11, B3, G7, F11, D12, F12,C5, C12, E12, B12, and A12 shown in FIG. 1A, respectively.

In FIG. 3A, bottom panel, the compounds, from left to right of theX-axis, are the compounds of the positions D9, C1, H1, H11, A3, G8, F1,D7, G12, G9, E6, C2, A1, G10, H10, B8, C3, B1, D1, C11, F3, G3, F10,E11, D5, A9, F6, G5, H8, D10, D2, H3, G6, E1, F5, F9, A7, D8, D11, G2,D3, G4, H2, E10, D6, C10, B4, A2, E3, H12, E9, A10, F2, F7, B7, G1, E7,A5, A4, B10, B5, A6, E2, F8, F4, H4, C9, D4, H9, C8, B9, A8, E8, C6, H7,G11, B2, E5, C4, B6, E4, C7, H6, H5, B3, B11, A11, G7, F11, C5, E12,D12, C12, F12, B12, and A12 shown in FIG. 1A, respectively.

In FIG. 3B, top panel, the compounds, from left to right of the X-axis,are the compounds of the positions D9, A3, C1, H1, F10, A9, A7, B8, H11,A1, E1, G8, E6, G10, B1, C11, G9, C2, F9, G5, A5, G3, C3, G12, D7, A10,G2, A2, E11, E10, A6, E3, H10, F1, F6, F3, G6, G1, G4, H3, B4, E9, F5,B10, H2, H8, A4, C10, B7, D5, D1, E7, F7, A8, D8, F8, D10, B5, D2, E2,D6, F4, D3, D11, C6, E5, C8, F2, G1, H12, C9, C4, E4, B9, H9, H4, E8,B6, D4, B2, C7, H7, G7, B3, H6, A11, F11, H5, C5, B11, E12, F12, D12,C12, B12, and A12 shown in FIG. 1A, respectively.

In FIG. 3B, bottom panel, the compounds, from left to right of theX-axis, are the compounds of the positions H1, D9, B8, A9, F10, G10,A10, G8, G12, B10, A3, F7, C1, H11, C11, G9, E10, H2, G5, F9, A7, D7,E3, E6, E11, G2, D5, D1, H3, F3, F1, F5, F6, G6, D2, E1, G3, G4, B1, D3,D8, F8, C2, A5, C10, B4, H12, H10, E9, F4, C3, A8, D10, B5, D11, B7, F2,D6, H8, A1, G11, A6, G1, E5, E7, H4, A2, C8, G7, E2, C6, H6, D4, E4, C9,A4, H9, A11, C7, B9, B2, D12, F12, B6, E8, C4, F11, H5, B3, C12, H7, C5,E12, B11, B12, and A12 shown in FIG. 1A, respectively.

In FIG. 4A, top panel, the compounds, from left to right of the X-axis,are the compounds of the positions C1, H1, A3, D9, G8, H3, H11, F3, H4,D7, A1, C11, C3, B1, A7, B2, H7, C2, B8, F10, D5, G12, D2, G9, D3, G5,A5, GIG, G2, G3, F6, F1, H10, D8, E11, F9, G6, E10, E6, A10, H8, C10,E3, D10, B10, A2, E1, D6, D11, D1, E7, B4, A4, F5, F4, H9, H12, H5, H2,E9, B7, F7, B5, A9, F2, G4, A6, G1, B9, F8, H6, E2, C7, D4, C6, C8, A11,E8, E5, B6, C9, C4, B11, G11, B3, A8, E4, G7, C5, F11, C12, D12, F12,E12, B12, and A12 shown in FIG. 1A, respectively.

In FIG. 44, bottom panel, the compounds, from left to right of theX-axis, are the compounds of the positions D9, C1, H1, A3, H11, F1, G9,C2, F3, G8, B1, H10, D7, D5, D1, D8, E6, C3, G3, H3, G10, B8, H8, G5,E11, G12, D2, G2, C11, F6, G6, A1, C10, A9, D10, F5, G4, F10, H2, F9,D6, E1, D3, D11, E10, F7, A5, B4, H12, B7, F2, E9, A2, E7, A7, G1, E3,B5, H4, A8, A10, F4, F8, B10, C8, C9, D4, A6, E2, A4, B9, H9, C4, G11,B2, E8, C7, C6, H7, B6, E5, H6, E4, H5, B3, G7, B11, C5, F11, A11, D12,C12, F12, E12, B12, and A12 shown in FIG. 1A, respectively.

In FIG. 4B, top panel, the compounds, from left to right of the X-axis,are the compounds of the positions D9, A3, C1, H1, A5, A9, A7, E6, B8,F10, G9, G2, C2, E1, H11, B1, A1, G8, C11, F9, C3, G4, C10, G3, G10, G6,G5, A2, A10, F3, D8, D1, A6, H2, H3, H10, E11, F5, D7, G1, F6, E10, E3,B5, D5, B7, G12, B10, B4, A4, E9, H8, F1, E7, E5, F8, F7, E2, D2, A8,D10, C4, C8, D3, G11, D6, F4, C9, D11, C6, B2, B6, E4, D4, H4, C7, E8,B9, F2, H9, B3, G7, H12, C5, H6, H7, F11, A11, H5, B11, D12, E12, C12,F12, A12, and B12 shown in FIG. 1A, respectively.

In FIG. 4B, bottom panel, the compounds, from left to right of theX-axis, are the compounds of the positions H1, D9, B8, C1, A9, A3, G9,A10, G10, F10, E6, G8, H2, F7, B10, C11, G2, G12, D8, H3, E10, F9, C10,G5, D5, H11, D1, A5, F3, A7, D7, G6, G3, E11, G4, D2, E3, F6, D3, C2,C3, F5, H10, C8, H12, E5, G11, C4, F8, B5, E9, B4, D11, F4, B7, A8, H4,D6, D4, E1, D10, B1, E2, C6, F2, C9, A6, E7, G7, C7, F1, B2, B3, H8, H9,G1, B6, C5, B9, E8, A2, H6, A4, E4, D12, C12, H5, F11, F12, A1, H7, A11,E12, B11, B12, and A12 shown in FIG. 1A, respectively.

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A compound of Formula (I):

or pharmaceutically acceptable salt thereof; wherein: R^(A) is hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(B) is hydrogen, substitutedor unsubstituted acyl, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or R^(A) and R^(B) are joined to form asubstituted or unsubstituted, carbocyclic ring, or a substituted orunsubstituted, heterocyclic ring; R^(C) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group; Ring B isphenylene; R¹ is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² and R³ are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —C(═O)R^(D1), —C(═O)OR^(D1), —C(═O)N(R^(D1))₂,or a nitrogen protecting group, wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogenprotecting group when attached to a nitrogen atom, or an oxygenprotecting group when attached to an oxygen atom, or two R^(D1) groupsare joined to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring, or a nitrogen protectinggroup when attached to a nitrogen atom; each instance of R^(B1) isindependently hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(B1a), —N(R^(B1a))₂,SR^(B1a), —CN, —SCN, —C(═NR^(B1a))R^(B1a), —C(═NR^(B1a))OR^(B1a),—C(═NR^(B1a))N(R^(B1a))₂, —C(═O)R^(B1a), —C(═O)OR^(B1a),—C(═O)N(R^(B1a))₂, —NO₂, —NR^(B1a)C(═O)R^(B1a), —NR^(B1a)C(═O)OR^(B1a),—NR^(B1a)C(═O)N(R^(B1a))₂, —OC(═O)R^(B1a), —OC(═O)OR^(B1a), or—OC(═O)N(R^(B1a))₂, wherein each instance of R^(B1a) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(B1a) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring; R^(B3) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(B3a), —N(R^(B3a))²,—SR^(B3a), —CN, —SCN, —C(═NR^(B3a))R^(B3a), —C(═NR^(B3a))OR^(B3a),—C(═NR^(B3a))N(R^(B3a))₂, —C(═O)R^(B3a), —C(═O)OR^(B3a),—C(═O)N(R^(B3a))₂, —NO₂, —NR^(B3a)C(═O)R^(B3a), —NR^(B3a)C(═O)OR^(B3a),—NR^(B3a)C(═O)N(R^(B3a))₂, —OC(═O)R^(B3a), —OC(═O)OR^(B3a), or—OC(═O)N(R^(B3a))₂, wherein each instance of R^(B3a) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two R^(B3a) groups are joined to form a substitutedor unsubstituted heterocyclic or substituted or unsubstituted heteroarylring; p is 0 or an integer between 1 and 4, inclusive; L¹ is a bond,

R^(a1) is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, or a nitrogen protecting group; and each instance of R^(c1)is independently hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(c1a), —N(R^(c1a))₂,—SR^(c1a), —CN, —C(═O)R^(c1a), —C(═O)OR^(c1a), —C(═O)N(R^(c1a))₂,—NR^(c1a)C(═O)R^(c1a), —NR^(c1a)C(═O)OR^(c1a),—NR^(c1a)C(═O)N(R^(c1a))₂, —OC(═O)R^(c1a), or —OC(═O)N(R^(c1a))₂,wherein each instance of R^(c1a) is independently hydrogen, substitutedor unsubstituted acyl, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, or a sulfur protecting group when attached to a sulfur atom, ortwo R^(c1a) groups are joined to form a substituted or unsubstitutedheterocyclic or substituted or unsubstituted heteroaryl ring; whereincarbocyclyl and a carbocyclic ring are a non-aromatic cyclic hydrocarbongroup having from 3 to 10 ring carbon atoms; wherein heterocyclyl and aheterocyclic ring are a 3- to 10-membered non-aromatic ring systemhaving ring carbon atoms and 1 to 4 ring heteroatoms, wherein eachheteroatom is independently selected from the group consisting ofnitrogen, oxygen, and sulfur; wherein heteroaryl and a heteroaryl ringare a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur; and whereinaryl is a monocyclic or polycyclic 4n+2 aromatic ring system having 6-14ring carbon atoms and zero heteroatoms; wherein acyl is independently—C(═O)R^(aa), —CHO, or —CO₂R^(aa); wherein each acyl, alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, heterocyclic ring, heteroaryl ring,aryl, and heteroaryl referred to above is substituted with one or moresubstituents at a carbon atom, the one or more substituents at thecarbon atom are independently selected from the substituents in Group(i); when any one of the heterocyclyl, heterocyclic ring, heteroaryl,and heteroaryl ring, referred to above is substituted with one or moresubstituents at a nitrogen atoms, the one or more substituents at thenitrogen atom are independently selected from the substituents in Group(ii); Group (i) consists of halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH,—OR^(aa), —ON(R^(bb))₂, —N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb),—SH, —SR^(aa), —SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂,—CO₂R^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂,—OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—OC(═NR^(bb))N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa),—SO₂OR^(aa), —OSO₂R^(aa), —S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —OP(R^(cc))₂, —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; or twogeminal hydrogens on a carbon atom are replaced with the group ═O, ═S,═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc); and Group (ii) consistsof hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂—SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(R^(aa))₂, —P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;wherein: each instance of R^(aa) is, independently, selected from C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(aa) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; eachinstance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(bb) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; each instance ofR^(cc) is, independently, selected from hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; each instance ofR^(dd) is, independently, selected from halogen, —CN, —NO₂, —N₃, —SO₂H,—SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂, —N(R^(ff))₃ ⁺X⁻,—N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee), —CO₂H,—CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂,—OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂,C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents canbe joined to form ═O or ═S; each instance of R^(ee) is, independently,selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups; each instance of R^(ff) is,independently, selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups; each instance of R^(gg) is,independently, halogen, —CN, —NO₂, —N₃—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl,—ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃ ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl),—N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl),—C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl),—OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl),—NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl),—NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂,—OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, —C(═S)NH(C₁₋₆ alkyl), —C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(C₁₋₆ alkyl)₂,—OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂₁₋₆ alkyl, C₁₋₆perhaloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, 5-10 membered heteroaryl; or two geminal R^(gg)substituents can be joined to form ═O or ═S; and X⁻ is a counterion,wherein the counterion is a halide ion, NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻,HSO₄ ⁻, a sulfonate ion, or a carboxylate ion.
 2. The compound of claim1, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein R¹ is substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.
 4. The compound of claim 1,wherein R² is substituted or unsubstituted C₁₋₆ alkyl or substituted orunsubstituted cycloalkyl.
 5. The compound of claim 1, wherein R² is asubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl ring.
 6. The compound of claim 1, wherein R³ is substitutedor unsubstituted C₁₋₆ alkyl.
 7. The compound of claim 1 wherein at leastone instance of R^(B1) is —OR^(B1a).
 8. The compound of claim 1, whereinL¹ is


9. The compound of claim 1, wherein


10. The compound of claim 1, wherein R^(A) is


11. The compound of claim 1, wherein R^(B) is


12. The compound of claim 1, wherein R^(A) and R^(B) are joined to forma substituted or unsubstituted, carbocyclic or heterocyclic ring. 13.The compound of claim 1, wherein R^(A) and R^(B) are joined to form amoiety of formula:


14. The compound of claim 1, wherein the compound is of formula:

wherein: R^(A) is

the compound is of formula:

wherein: R^(A) or R^(B) is

or the compound is of formula:

wherein R^(A) and R^(B) are joined to form a moiety of formula:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and optionally a pharmaceutically acceptableexcipient.
 16. A method for male contraception, the method comprisingadministering to a male subject in need thereof an effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 17.The compound of claim 1, wherein R^(A) is substituted or unsubstitutedaryl.
 18. The compound of claim 1, wherein R^(A) is substituted orunsubstituted heterocyclyl.
 19. The compound of claim 1, wherein R^(B)is substituted or unsubstituted aryl.